Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting CDK4 and CDK6 in cancer

Nature Reviews Cancer volume 22, pages 356–372 (2022)Cite this article

Subjects

Abstract

Cyclin-dependent kinase 4 (CDK4) and CDK6 are critical mediators of cellular transition into S phase and are important for the initiation, growth and survival of many cancer types. Pharmacological inhibitors of CDK4/6 have rapidly become a new standard of care for patients with advanced hormone receptor-positive breast cancer. As expected, CDK4/6 inhibitors arrest sensitive tumour cells in the G1 phase of the cell cycle. However, the effects of CDK4/6 inhibition are far more wide-reaching. New insights into their mechanisms of action have triggered identification of new therapeutic opportunities, including the development of novel combination regimens, expanded application to a broader range of cancers and use as supportive care to ameliorate the toxic effects of other therapies. Exploring these new opportunities in the clinic is an urgent priority, which in many cases has not been adequately addressed. Here, we provide a framework for conceptualizing the activity of CDK4/6 inhibitors in cancer and explain how this framework might shape the future clinical development of these agents. We also discuss the biological underpinnings of CDK4/6 inhibitor resistance, an increasingly common challenge in clinical oncology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The CDK4 and CDK6 pathway in cancer.
Fig. 2: A conceptual framework to understand the effects of CDK4 and CDK6 inhibitors in cancer.
Fig. 3: Effect of CDK4 and CDK6 inhibition upon tumour cell-intrinsic and tumour cell-extrinsic signalling pathways.
Fig. 4: CDK4 and CDK6 inhibitors exert differential effects in distinct immune cell populations.
Fig. 5: Novel approaches for the use of CDK4 and CDK6 inhibitors.

Similar content being viewed by others

References

  1. Asghar, U., Witkiewicz, A. K., Turner, N. C. & Knudsen, E. S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov. 14, 130–146 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Losiewicz, M. D., Carlson, B. A., Kaur, G., Sausville, E. A. & Worland, P. J. Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275. Biochem. Biophys. Res. Commun. 201, 589–595 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Sanchez-Martinez, C., Lallena, M. J., Sanfeliciano, S. G. & de Dios, A. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs: recent advances (2015-2019). Bioorg. Med. Chem. Lett. 29, 126637 (2019).

    Article  CAS  PubMed  Google Scholar 

  4. Malumbres, M. Cyclin-dependent kinases. Genome Biol. 15, 122 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Malumbres, M. et al. Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 118, 493–504 (2004). Using Cdk4 and Cdk6 double-knockout mice, this study establishes that mammalian cells can proliferate in the absence of both CDK4 and CDK6, demonstrating a plasticity of cyclin–CDK networks that has implications for CDK4/6 inhibitor resistance.

    Article  CAS  PubMed  Google Scholar 

  6. Xiong, Y., Zhang, H. & Beach, D. D type cyclins associate with multiple protein kinases and the DNA replication and repair factor PCNA. Cell 71, 505–514 (1992).

    Article  CAS  PubMed  Google Scholar 

  7. Santamaria, D. et al. Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448, 811–815 (2007).

    Article  CAS  PubMed  Google Scholar 

  8. Herrera-Abreu, M. T. et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 76, 2301–2313 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. O’Leary, B., Finn, R. S. & Turner, N. C. Treating cancer with selective CDK4/6 inhibitors. Nat. Rev. Clin. Oncol. 13, 417–430 (2016).

    Article  PubMed  CAS  Google Scholar 

  10. Puyol, M. et al. A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma. Cancer Cell 18, 63–73 (2010).

    Article  CAS  PubMed  Google Scholar 

  11. Yu, Q. et al. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 9, 23–32 (2006). This research establishes that cyclin D1-associated CDK4 is necessary for the formation and continued proliferation of mammary carcinomas driven by Erbb2.

    Article  CAS  PubMed  Google Scholar 

  12. Choi, Y. J. et al. The requirement for cyclin D function in tumor maintenance. Cancer Cell 22, 438–451 (2012). This study provides in vivo evidence that CDK4/6 inhibitors induce a senescence-like phenotype in mammary carcinomas but cellular apoptosis in T cell leukaemias.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fry, D. W. et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol. Cancer Ther. 3, 1427–1438 (2004).

    CAS  PubMed  Google Scholar 

  14. Spring, L. M. et al. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. Lancet 395, 817–827 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. Martinez-Alonso, D. & Malumbres, M. Mammalian cell cycle cyclins. Semin. Cell Dev. Biol. 107, 28–35 (2020).

    Article  CAS  PubMed  Google Scholar 

  16. Xiong, Y., Connolly, T., Futcher, B. & Beach, D. Human D-type cyclin. Cell 65, 691–699 (1991).

    Article  CAS  PubMed  Google Scholar 

  17. Lew, D. J., Dulic, V. & Reed, S. I. Isolation of three novel human cyclins by rescue of G1 cyclin (Cln) function in yeast. Cell 66, 1197–1206 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. Matsushime, H., Roussel, M. F., Ashmun, R. A. & Sherr, C. J. Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 65, 701–713 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Pardee, A. B. A restriction point for control of normal animal cell proliferation. Proc. Natl Acad. Sci. USA 71, 1286–1290 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Aktas, H., Cai, H. & Cooper, G. M. Ras links growth factor signaling to the cell cycle machinery via regulation of cyclin D1 and the Cdk inhibitor p27KIP1. Mol. Cell. Biol. 17, 3850–3857 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Peeper, D. S. et al. Ras signalling linked to the cell-cycle machinery by the retinoblastoma protein. Nature 386, 177–181 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Diehl, J. A., Cheng, M., Roussel, M. F. & Sherr, C. J. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12, 3499–3511 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Matsushime, H. et al. Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 71, 323–334 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Kato, J., Matsushime, H., Hiebert, S. W., Ewen, M. E. & Sherr, C. J. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev. 7, 331–342 (1993).

    Article  CAS  PubMed  Google Scholar 

  25. Meyerson, M. & Harlow, E. Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol. Cell. Biol. 14, 2077–2086 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Weintraub, S. J., Prater, C. A. & Dean, D. C. Retinoblastoma protein switches the E2F site from positive to negative element. Nature 358, 259–261 (1992).

    Article  CAS  PubMed  Google Scholar 

  27. Weintraub, S. J. et al. Mechanism of active transcriptional repression by the retinoblastoma protein. Nature 375, 812–815 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Hiebert, S. W., Chellappan, S. P., Horowitz, J. M. & Nevins, J. R. The interaction of RB with E2F coincides with an inhibition of the transcriptional activity of E2F. Genes Dev. 6, 177–185 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Sellers, W. R., Rodgers, J. W. & Kaelin, W. G. Jr. A potent transrepression domain in the retinoblastoma protein induces a cell cycle arrest when bound to E2F sites. Proc. Natl Acad. Sci. USA 92, 11544–11548 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Chicas, A. et al. H3K4 demethylation by Jarid1a and Jarid1b contributes to retinoblastoma-mediated gene silencing during cellular senescence. Proc. Natl Acad. Sci. USA 109, 8971–8976 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Luo, R. X., Postigo, A. A. & Dean, D. C. Rb interacts with histone deacetylase to repress transcription. Cell 92, 463–473 (1998).

    Article  CAS  PubMed  Google Scholar 

  32. Zhou, Y. et al. HDAC5 loss impairs RB repression of pro-oncogenic genes and confers CDK4/6 inhibitor resistance in cancer. Cancer Res. 81, 1486–1499 (2021).

    Article  CAS  PubMed  Google Scholar 

  33. Harbour, J. W., Luo, R. X., Dei Santi, A., Postigo, A. A. & Dean, D. C. Cdk phosphorylation triggers sequential intramolecular interactions that progressively block Rb functions as cells move through G1. Cell 98, 859–869 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Goodrich, D. W., Wang, N. P., Qian, Y. W., Lee, E. Y. & Lee, W. H. The retinoblastoma gene product regulates progression through the G1 phase of the cell cycle. Cell 67, 293–302 (1991).

    Article  CAS  PubMed  Google Scholar 

  35. Serrano, M., Hannon, G. J. & Beach, D. A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 366, 704–707 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Stepanova, L., Leng, X., Parker, S. B. & Harper, J. W. Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. Genes Dev. 10, 1491–1502 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Zhao, Q., Boschelli, F., Caplan, A. J. & Arndt, K. T. Identification of a conserved sequence motif that promotes Cdc37 and cyclin D1 binding to Cdk4. J. Biol. Chem. 279, 12560–12564 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Lamphere, L. et al. Interaction between Cdc37 and Cdk4 in human cells. Oncogene 14, 1999–2004 (1997).

    Article  CAS  PubMed  Google Scholar 

  39. Harper, J. W., Adami, G. R., Wei, N., Keyomarsi, K. & Elledge, S. J. The p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases. Cell 75, 805–816 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Xiong, Y. et al. p21 is a universal inhibitor of cyclin kinases. Nature 366, 701–704 (1993).

    Article  CAS  PubMed  Google Scholar 

  41. Toyoshima, H. & Hunter, T. p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78, 67–74 (1994).

    Article  CAS  PubMed  Google Scholar 

  42. LaBaer, J. et al. New functional activities for the p21 family of CDK inhibitors. Genes Dev. 11, 847–862 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Guiley, K. Z. et al. p27 allosterically activates cyclin-dependent kinase 4 and antagonizes palbociclib inhibition. Science 366, eaaw2106 (2019). This study proposes an alternative hypothesis for the mechanism of action of CDK4/6 inhibitors, positing that these agents do not directly inhibit CDK4 but rather sequester monomeric CDK4, thereby freeing p21 to bind and inhibit CDK2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. McConnell, B. B., Gregory, F. J., Stott, F. J., Hara, E. & Peters, G. Induced expression of p16(INK4a) inhibits both CDK4- and CDK2-associated kinase activity by reassortment of cyclin-CDK-inhibitor complexes. Mol. Cell. Biol. 19, 1981–1989 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bagui, T. K., Mohapatra, S., Haura, E. & Pledger, W. J. P27Kip1 and p21Cip1 are not required for the formation of active D cyclin-cdk4 complexes. Mol. Cell. Biol. 23, 7285–7290 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Sugimoto, M. et al. Activation of cyclin D1-kinase in murine fibroblasts lacking both p21(Cip1) and p27(Kip1). Oncogene 21, 8067–8074 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Cerqueira, A. et al. Genetic characterization of the role of the Cip/Kip family of proteins as cyclin-dependent kinase inhibitors and assembly factors. Mol. Cell. Biol. 34, 1452–1459 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Pennycook, B. R. & Barr, A. R. Palbociclib-mediated cell cycle arrest can occur in the absence of the CDK inhibitors p21 and p27. Open Biol. 11, 210125 (2021). Using a series of genetic manipulations in cell-based models, this study demonstrates that p21 and p27 are not required for cells to enter or remain in palbociclib-mediated G1 arrest (providing an alternative hypothesis to that presented in Guiley et al. (2019)).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tetsu, O. & McCormick, F. Proliferation of cancer cells despite CDK2 inhibition. Cancer Cell 3, 233–245 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Gong, X. et al. Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib. Cancer Cell 32, 761–776.e6 (2017). This study provides a reference data set for the sensitivity of human cancer cell lines to CDK4/6 inhibitors (abemaciclib, n = 560; palbociclib, n = 492) and highlights a series of genomic alterations that are associated with sensitivity or resistance to these agents.

    Article  CAS  PubMed  Google Scholar 

  51. Seto, M. et al. Gene rearrangement and overexpression of PRAD1 in lymphoid malignancy with t(11;14)(q13;q32) translocation. Oncogene 7, 1401–1406 (1992).

    CAS  PubMed  Google Scholar 

  52. Wiestner, A. et al. Point mutations and genomic deletions in CCND1 create stable truncated cyclin D1 mRNAs that are associated with increased proliferation rate and shorter survival. Blood 109, 4599–4606 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Li, M. et al. Kaposi’s sarcoma-associated herpesvirus encodes a functional cyclin. J. Virol. 71, 1984–1991 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Santra, M. K., Wajapeyee, N. & Green, M. R. F-box protein FBXO31 mediates cyclin D1 degradation to induce G1 arrest after DNA damage. Nature 459, 722–725 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Simoneschi, D. et al. CRL4(AMBRA1) is a master regulator of D-type cyclins. Nature 592, 789–793 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Moreno-Bueno, G. et al. Cyclin D1 gene (CCND1) mutations in endometrial cancer. Oncogene 22, 6115–6118 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Barbash, O. et al. Mutations in Fbx4 inhibit dimerization of the SCF(Fbx4) ligase and contribute to cyclin D1 overexpression in human cancer. Cancer Cell 14, 68–78 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Benzeno, S. et al. Identification of mutations that disrupt phosphorylation-dependent nuclear export of cyclin D1. Oncogene 25, 6291–6303 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Jones, S. M. & Kazlauskas, A. Growth-factor-dependent mitogenesis requires two distinct phases of signalling. Nat. Cell Biol. 3, 165–172 (2001).

    Article  CAS  PubMed  Google Scholar 

  60. Choi, Y. J. & Anders, L. Signaling through cyclin D-dependent kinases. Oncogene 33, 1890–1903 (2014).

    Article  CAS  PubMed  Google Scholar 

  61. Schmidt, M. et al. Cell cycle inhibition by FoxO forkhead transcription factors involves downregulation of cyclin D. Mol. Cell. Biol. 22, 7842–7852 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Muise-Helmericks, R. C. et al. Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J. Biol. Chem. 273, 29864–29872 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Averous, J., Fonseca, B. D. & Proud, C. G. Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1. Oncogene 27, 1106–1113 (2008).

    Article  CAS  PubMed  Google Scholar 

  64. Rosenwald, I. B., Lazaris-Karatzas, A., Sonenberg, N. & Schmidt, E. V. Elevated levels of cyclin D1 protein in response to increased expression of eukaryotic initiation factor 4E. Mol. Cell. Biol. 13, 7358–7363 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Prall, O. W., Sarcevic, B., Musgrove, E. A., Watts, C. K. & Sutherland, R. L. Estrogen-induced activation of Cdk4 and Cdk2 during G1-S phase progression is accompanied by increased cyclin D1 expression and decreased cyclin-dependent kinase inhibitor association with cyclin E-Cdk2. J. Biol. Chem. 272, 10882–10894 (1997). This study demonstrates that oestradiol directly stimulates CCND1 expression in human breast cancer cells, clarifying a key mechanism underlying oestradiol-driven mitogenic signalling and strengthening the rationale for using CDK4/6 inhibitors to treat HR-positive breast cancer.

    Article  CAS  PubMed  Google Scholar 

  66. Xu, Y., Chen, S. Y., Ross, K. N. & Balk, S. P. Androgens induce prostate cancer cell proliferation through mammalian target of rapamycin activation and post-transcriptional increases in cyclin D proteins. Cancer Res. 66, 7783–7792 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Tetsu, O. & McCormick, F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999).

    Article  CAS  PubMed  Google Scholar 

  68. Bouchard, C. et al. Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27. EMBO J. 18, 5321–5333 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Ronchini, C. & Capobianco, A. J. Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic). Mol. Cell. Biol. 21, 5925–5934 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sicinska, E. et al. Requirement for cyclin D3 in lymphocyte development and T cell leukemias. Cancer Cell 4, 451–461 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Mizuno, T. et al. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes. Oncogene 31, 5117–5122 (2012).

    Article  CAS  PubMed  Google Scholar 

  72. Li, Z. et al. Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway. Cancer Cell 34, 893–905.e8 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Li, F. et al. YAP1-mediated CDK6 activation confers radiation resistance in esophageal cancer - rationale for the combination of YAP1 and CDK4/6 inhibitors in esophageal Cancer. Clin. Cancer Res. 25, 2264–2277 (2019).

    Article  CAS  PubMed  Google Scholar 

  74. Sicinski, P. et al. Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82, 621–630 (1995).

    Article  CAS  PubMed  Google Scholar 

  75. Jeselsohn, R. et al. Cyclin D1 kinase activity is required for the self-renewal of mammary stem and progenitor cells that are targets of MMTV-ErbB2 tumorigenesis. Cancer Cell 17, 65–76 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Sawai, C. M. et al. Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia. Cancer Cell 22, 452–465 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang, T. C. et al. Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369, 669–671 (1994).

    Article  CAS  PubMed  Google Scholar 

  78. Musgrove, E. A., Lee, C. S., Buckley, M. F. & Sutherland, R. L. Cyclin D1 induction in breast cancer cells shortens G1 and is sufficient for cells arrested in G1 to complete the cell cycle. Proc. Natl Acad. Sci. USA 91, 8022–8026 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Anders, L. et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 20, 620–634 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Musgrove, E. A., Caldon, C. E., Barraclough, J., Stone, A. & Sutherland, R. L. Cyclin D as a therapeutic target in cancer. Nat. Rev. Cancer 11, 558–572 (2011).

    Article  CAS  PubMed  Google Scholar 

  81. Yu, Q., Geng, Y. & Sicinski, P. Specific protection against breast cancers by cyclin D1 ablation. Nature 411, 1017–1021 (2001). This study demonstrates a specific role for cyclin D1 in the initiation of mouse mammary tumours driven by Erbb2 or Hras, signifying a potential role for inhibiting cyclin D1 function in breast cancer.

    Article  CAS  PubMed  Google Scholar 

  82. Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003).

    Article  CAS  PubMed  Google Scholar 

  83. Wang, H. et al. The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival. Nature 546, 426–430 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. VanderWel, S. N. et al. Pyrido[2,3-d]pyrimidin-7-ones as specific inhibitors of cyclin-dependent kinase 4. J. Med. Chem. 48, 2371–2387 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Besong, G. et al. Pyrrolopyrimidine compounds and their uses. US Patent 8,685,980 (2014).

  86. Gelbert, L. M. et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest. N. Drugs 32, 825–837 (2014).

    Article  CAS  Google Scholar 

  87. Sanchez-Martinez, C., Gelbert, L. M., Lallena, M. J. & de Dios, A. Cyclin dependent kinase (CDK) inhibitors as anticancer drugs. Bioorg. Med. Chem. Lett. 25, 3420–3435 (2015).

    Article  CAS  PubMed  Google Scholar 

  88. Bisi, J. E., Sorrentino, J. A., Roberts, P. J., Tavares, F. X. & Strum, J. C. Preclinical characterization of G1T28: a novel CDK4/6 inhibitor for reduction of chemotherapy-induced myelosuppression. Mol. Cancer Ther. 15, 783–793 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. He, S. et al. Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion. Sci. Transl Med. 9, eaal3986 (2017). This study demonstrates that trilaciclib induces transient inhibition of haematopoietic stem cells in mice and humans, providing a rationale for its use as a myelopreservative in patients receiving cytotoxic chemotherapy.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Wu, X. et al. Distinct CDK6 complexes determine tumor cell response to CDK4/6 inhibitors and degraders. Nat. Cancer 2, 429–443 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Sumi, N. J., Kuenzi, B. M., Knezevic, C. E., Remsing Rix, L. L. & Rix, U. Chemoproteomics reveals novel protein and lipid kinase targets of clinical CDK4/6 inhibitors in lung cancer. ACS Chem. Biol. 10, 2680–2686 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hafner, M. et al. Multiomics profiling establishes the polypharmacology of FDA-approved CDK4/6 inhibitors and the potential for differential clinical activity. Cell Chem. Biol. 26, 1067–1080.e8 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Litchfield, L. M. et al. Combined inhibition of PIM and CDK4/6 suppresses both mTOR signaling and Rb phosphorylation and potentiates PI3K inhibition in cancer cells. Oncotarget 11, 1478–1492 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  94. Torres-Guzmán, R. et al. Preclinical characterization of abemaciclib in hormone receptor positive breast cancer. Oncotarget 8, 69493–69507 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Cousins, E. M. et al. Competitive kinase enrichment proteomics reveals that abemaciclib inhibits GSK3β and activates WNT signaling. Mol. Cancer Res. 16, 333–344 (2018).

    Article  CAS  PubMed  Google Scholar 

  96. Knudsen, E. S., Hutcheson, J., Vail, P. & Witkiewicz, A. K. Biological specificity of CDK4/6 inhibitors: dose response relationship, in vivo signaling, and composite response signature. Oncotarget 8, 43678–43691 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Leonard, J. P. et al. Selective CDK4/6 inhibition with tumor responses by PD0332991 in patients with mantle cell lymphoma. Blood 119, 4597–4607 (2012).

    Article  CAS  PubMed  Google Scholar 

  98. Finn, R. S. et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 11, R77 (2009). This preclinical study demonstrates that human breast cancer cell lines representing luminal, HR-positive subtypes (both HER2 positive and HER2 negative) are more sensitive to CDK4/6 inhibition than those representing non-luminal or basal subtypes.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. DeMichele, A. et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin. Cancer Res. 21, 995–1001 (2015).

    Article  CAS  PubMed  Google Scholar 

  100. Patnaik, A. et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov. 6, 740–753 (2016). This phase I/II clinical trial demonstrates clinical activity for abemaciclib monotherapy in subsets of patients with breast cancer, non-small-cell lung cancer and melanoma.

    Article  CAS  PubMed  Google Scholar 

  101. Hurvitz, S. et al. Treatment with abemaciclib modulates the immune response in gene expression analysis of the neoMONARCH neoadjuvant study of abemaciclib in postmenopausal women with HR+, HER2 negative breast cancer [abstract]. Cancer Res. 79 (Suppl. 4), PD2-10 (2019).

    Google Scholar 

  102. Malorni, L. et al. Palbociclib as single agent or in combination with the endocrine therapy received before disease progression for estrogen receptor-positive, HER2-negative metastatic breast cancer: TREnd trial. Ann. Oncol. 29, 1748–1754 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Dickler, M. N. et al. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR(+)/HER2(-) metastatic breast aancer. Clin. Cancer Res. 23, 5218–5224 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Ma, C. X. et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. Clin. Cancer Res. 23, 4055–4065 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Johnston, S. et al. Randomized Phase II study evaluating palbociclib in addition to letrozole as neoadjuvant therapy in estrogen receptor-positive early breast cancer: PALLET trial. J. Clin. Oncol. 37, 178–189 (2019).

    Article  CAS  PubMed  Google Scholar 

  106. Tripathy, D. et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial. Lancet Oncol. 19, 904–915 (2018).

    Article  CAS  PubMed  Google Scholar 

  107. Finn, R. S. et al. Palbociclib and letrozole in advanced breast cancer. N. Engl. J. Med. 375, 1925–1936 (2016).

    Article  CAS  PubMed  Google Scholar 

  108. Hortobagyi, G. N. et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N. Engl. J. Med. 75, 1738–1748 (2016).

    Article  PubMed  Google Scholar 

  109. Goetz, M. P. et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer. J. Clin. Oncol. 35, 3638–3646 (2017). Together with Finn et al. (2016) and Hortobagyi et al. (2016), this study presents data from randomized phase III clinical trials indicating that the addition of CDK4/6 inhibitors to first-line endocrine therapy significantly prolongs progression-free survival for patients with advanced, HR-positive breast cancer.

    Article  CAS  PubMed  Google Scholar 

  110. Turner, N. C. et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer. N. Engl. J. Med. 379, 1926–1936 (2018).

    Article  CAS  PubMed  Google Scholar 

  111. Sledge, G. W. Jr et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, erbb2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial. JAMA Oncol. 6, 116–124 (2020).

    Article  PubMed  Google Scholar 

  112. Slamon, D. J. et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer. N. Engl. J. Med. 382, 514–524 (2020).

    Article  CAS  PubMed  Google Scholar 

  113. Sledge, G. W. Jr. et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J. Clin. Oncol. 35, 2875–2884 (2017).

    Article  CAS  PubMed  Google Scholar 

  114. Turner, N. C. et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 373, 209–219 (2015).

    Article  CAS  PubMed  Google Scholar 

  115. Toogood, P. L. et al. Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6. J. Med. Chem. 48, 2388–2406 (2005).

    Article  CAS  PubMed  Google Scholar 

  116. Dean, J. L., Thangavel, C., McClendon, A. K., Reed, C. A. & Knudsen, E. S. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 29, 4018–4032 (2010).

    Article  CAS  PubMed  Google Scholar 

  117. Arnedos, M. et al. Modulation of Rb phosphorylation and antiproliferative response to palbociclib: the preoperative-palbociclib (POP) randomized clinical trial. Ann. Oncol. 29, 1755–1762 (2018).

    Article  CAS  PubMed  Google Scholar 

  118. Infante, J. R. et al. A phase I study of the cyclin-dependent kinase 4/6 inhibitor ribociclib (LEE011) in patients with advanced solid tumors and lymphomas. Clin. Cancer Res. 22, 5696–5705 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Konecny, G. E. et al. Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin. Cancer Res. 17, 1591–1602 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dimova, D. K. & Dyson, N. J. The E2F transcriptional network: old acquaintances with new faces. Oncogene 24, 2810–2826 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Kimura, H., Nakamura, T., Ogawa, T., Tanaka, S. & Shiota, K. Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways. Nucleic Acids Res. 31, 3101–3113 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Ren, B. et al. E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev. 16, 245–256 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Annicotte, J. S. et al. The CDK4-pRB-E2F1 pathway controls insulin secretion. Nat. Cell Biol. 11, 1017–1023 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Blanchet, E. et al. E2F transcription factor-1 regulates oxidative metabolism. Nat. Cell Biol. 13, 1146–1152 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Tsai, K. Y. et al. Mutation of E2f-1 suppresses apoptosis and inappropriate S phase entry and extends survival of Rb-deficient mouse embryos. Mol. Cell 2, 293–304 (1998).

    Article  CAS  PubMed  Google Scholar 

  126. Ziebold, U., Reza, T., Caron, A. & Lees, J. A. E2F3 contributes both to the inappropriate proliferation and to the apoptosis arising in Rb mutant embryos. Genes Dev. 15, 386–391 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Müller, H. et al. E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. Genes Dev. 15, 267–285 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Crozier, L. et al. CDK4/6 inhibitors induce replication stress to cause long-term cell cycle withdrawal. EMBO J. https://doi.org/10.15252/embj.2021108599 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Dean, J. L., McClendon, A. K. & Knudsen, E. S. Modification of the DNA damage response by therapeutic CDK4/6 inhibition. J. Biol. Chem. 287, 29075–29087 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Goel, S. et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature 548, 471–475 (2017). This is the first study to demonstrate that CDK4/6 inhibitors can stimulate antitumour immune responses, underpinning synergy upon dual inhibition of CDK4/6 and inhibitory immune checkpoints.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Salvador-Barbero, B. et al. CDK4/6 inhibitors impair recovery from cytotoxic chemotherapy in pancreatic adenocarcinoma. Cancer Cell 37, 340–353.e6 (2020). This preclinical study demonstrates that the impact of combined CDK4/6 inhibition and cytotoxic chemotherapy is sequence dependent, providing a rationale for the development of therapeutic regimens in which CDK4/6 inhibitors are administered after antimitotic chemotherapy (for example, taxanes).

    Article  CAS  PubMed  Google Scholar 

  132. Thangavel, C. et al. Therapeutic challenge with a CDK 4/6 inhibitor induces an RB-dependent SMAC-mediated apoptotic response in non-small cell lung cancer. Clin. Cancer Res. 24, 1402–1414 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Michaud, K. et al. Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res. 70, 3228–3238 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Thangavel, C. et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr. Relat. Cancer 18, 333–345 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Yoshida, A., Lee, E. K. & Diehl, J. A. Induction of therapeutic senescence in vemurafenib-resistant melanoma by extended inhibition of CDK4/6. Cancer Res. 76, 2990–3002 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Shay, J. W., Pereira-Smith, O. M. & Wright, W. E. A role for both RB and p53 in the regulation of human cellular senescence. Exp. Cell Res. 196, 33–39 (1991).

    Article  CAS  PubMed  Google Scholar 

  137. Acevedo, M. et al. A CDK4/6-dependent epigenetic mechanism protects cancer cells from PML-induced senescence. Cancer Res. 76, 3252–3264 (2016).

    Article  CAS  PubMed  Google Scholar 

  138. Rubio, C. et al. CDK4/6 inhibitor as a novel therapeutic approach for advanced bladder cancer independently of RB1 status. Clin. Cancer Res. 25, 390–402 (2019).

    Article  CAS  PubMed  Google Scholar 

  139. Gorgoulis, V. et al. Cellular senescence: defining a path forward. Cell 179, 813–827 (2019).

    Article  CAS  PubMed  Google Scholar 

  140. Guan, X. et al. Stromal senescence by prolonged CDK4/6 inhibition potentiates tumor growth. Mol. Cancer Res. 15, 237–249 (2017).

    Article  CAS  PubMed  Google Scholar 

  141. Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Watt, A. C. et al. CDK4/6 inhibition reprograms the breast cancer enhancer landscape by stimulating AP-1 transcriptional activity. Nat. Cancer 2, 34–48 (2021). This study uses in vitro and in vivo models, as well as clinical specimens, to establish that CDK4/6 inhibitor-induced ‘senescence’ is accompanied by remodelling of cancer cell chromatin and that the consequent transcriptional changes underpin key effects of these drugs in breast cancer.

    Article  CAS  PubMed  Google Scholar 

  143. Tasdemir, N. et al. BRD4 connects enhancer remodeling to senescence immune surveillance. Cancer Discov. 6, 612–629 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Martinez-Zamudio, R. I. et al. AP-1 imprints a reversible transcriptional programme of senescent cells. Nat. Cell Biol. 22, 842–855 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Walter, D. M. et al. RB constrains lineage fidelity and multiple stages of tumour progression and metastasis. Nature 569, 423–427 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ruscetti, M. et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science 362, 1416–1422 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Ruscetti, M. et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell 181, 424–441.e21 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Haines, E. et al. Palbociclib resistance confers dependence on an FGFR-MAP kinase-mTOR-driven pathway in KRAS-mutant non-small cell lung cancer. Oncotarget 9, 31572–31589 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Kovatcheva, M. et al. MDM2 turnover and expression of ATRX determine the choice between quiescence and senescence in response to CDK4 inhibition. Oncotarget 6, 8226–8243 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Zou, X. et al. Cdk4 disruption renders primary mouse cells resistant to oncogenic transformation, leading to Arf/p53-independent senescence. Genes Dev. 16, 2923–2934 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Esteban-Burgos, L. et al. Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas. Proc. Natl Acad. Sci. USA 117, 24415–24426 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Uras, I. Z. et al. Palbociclib treatment of FLT3-ITD+AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6. Blood 127, 2890–2902 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Goel, S. et al. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell 29, 255–269 (2016). This study outlines the molecular rationale for combined inhibition of CDK4/6 and upstream mitogenic signals, and also provides the first evidence that abemaciclib can delay the relapse of dormant cancer cells in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Dick, F. A., Goodrich, D. W., Sage, J. & Dyson, N. J. Non-canonical functions of the RB protein in cancer. Nat. Rev. Cancer 18, 442–451 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Nead, M. A., Baglia, L. A., Antinore, M. J., Ludlow, J. W. & McCance, D. J. Rb binds c-Jun and activates transcription. EMBO J. 17, 2342–2352 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Singh, P., Coe, J. & Hong, W. A role for retinoblastoma protein in potentiating transcriptional activation by the glucocorticoid receptor. Nature 374, 562–565 (1995).

    Article  CAS  PubMed  Google Scholar 

  157. Liu, L. et al. G1 cyclins link proliferation, pluripotency and differentiation of embryonic stem cells. Nat. Cell Biol. 19, 177–188 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Deng, J. et al. CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov. 8, 216–233 (2018). This study highlights that CDK4/6 inhibitor-induced immune stimulation is driven, in part, by direct effects on effector T lymphocytes.

    Article  CAS  PubMed  Google Scholar 

  159. Yin, Q. et al. CDK4/6 regulate lysosome biogenesis through TFEB/TFE3. J. Cell Biol. 219, e201911036 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Liu, T. et al. CDK4/6-dependent activation of DUB3 regulates cancer metastasis through SNAIL1. Nat. Commun. 8, 13923 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Zhang, J. et al. Cyclin D-CDK4 kinase destabilizes PD-L1 via cullin 3-SPOP to control cancer immune surveillance. Nature 553, 91–95 (2018).

    Article  CAS  PubMed  Google Scholar 

  162. Romero-Pozuelo, J., Demetriades, C., Schroeder, P. & Teleman, A. A. CycD/Cdk4 and discontinuities in Dpp signaling activate TORC1 in the Drosophila wing disc. Dev. Cell 42, 376–387.e5 (2017).

    Article  CAS  PubMed  Google Scholar 

  163. Romero-Pozuelo, J., Figlia, G., Kaya, O., Martin-Villalba, A. & Teleman, A. A. Cdk4 and Cdk6 couple the cell-cycle machinery to cell growth via mTORC1. Cell Rep. 31, 107504 (2020).

    Article  CAS  PubMed  Google Scholar 

  164. Lai, A. Y. et al. CDK4/6 inhibition enhances antitumor efficacy of chemotherapy and immune checkpoint inhibitor combinations in preclinical models and enhances T-cell activation in patients with SCLC receiving chemotherapy. J. Immunother. Cancer 8, e000847 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Fang, J. S. et al. Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification. Nat. Commun. 8, 2149 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Wang, B. et al. Pharmacological CDK4/6 inhibition reveals a p53-dependent senescent state with restricted toxicity. EMBO J. https://doi.org/10.15252/embj.2021108946 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Goel, S., DeCristo, M. J., McAllister, S. S. & Zhao, J. J. CDK4/6 inhibition in cancer: beyond cell cycle arrest. Trends Cell Biol. 28, 911–925 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Wardell, S. E. et al. Efficacy of SERD/SERM hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy–resistant breast cancer. Clin. Cancer Res. 21, 5121–5130 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Andreano, K. J. et al. G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer. Breast Cancer Res. Treat. 180, 635–646 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. O’Brien, N. et al. Preclinical activity of abemaciclib alone or in combination with antimitotic and targeted therapies in breast cancer. Mol. Cancer Ther. 17, 897–907 (2018).

    Article  PubMed  CAS  Google Scholar 

  171. Miller, T. W. et al. ERα-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 1, 338–351 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Zwijsen, R. M. et al. CDK-independent activation of estrogen receptor by cyclin D1. Cell 88, 405–415 (1997).

    Article  CAS  PubMed  Google Scholar 

  173. Vora, S. R. et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26, 136–149 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Hallin, J. et al. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 10, 54–71 (2020).

    Article  CAS  PubMed  Google Scholar 

  175. Lou, K. et al. KRASG12C inhibition produces a driver-limited state revealing collateral dependencies. Sci. Signal. 12, eaaw9450 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Kwong, L. N. et al. Oncogenic NRAS signaling differentially regulates survival and proliferation in melanoma. Nat. Med. 18, 1503–1510 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Heilmann, A. M. et al. CDK4/6 and IGF1 receptor inhibitors synergize to suppress the growth of p16INK4A-deficient pancreatic cancers. Cancer Res. 74, 3947–3958 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Formisano, L. et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat. Commun. 10, 1373 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Tong, Z. et al. Functional genomics identifies predictive markers and clinically actionable resistance mechanisms to CDK4/6 inhibition in bladder cancer. J. Exp. Clin. Cancer Res. 38, 322 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Jansen, V. M. et al. Kinome-wide RNA interference screen reveals a role for PDK1 in acquired resistance to CDK4/6 inhibition in ER-positive breast cancer. Cancer Res. 77, 2488–2499 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Guenther, L. M. et al. A combination CDK4/6 and IGF1R inhibitor strategy for Ewing sarcoma. Clin. Cancer Res. 25, 1343–1357 (2019).

    Article  CAS  PubMed  Google Scholar 

  182. Zhao, M. et al. Combining neratinib with CDK4/6, mTOR and MEK inhibitors in models of HER2-positive cancer. Clin. Cancer Res. 27, 1681–1694 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. de Leeuw, R. et al. MAPK reliance via acquired CDK4/6 inhibitor resistance in cancer. Clin. Cancer Res. 24, 4201–4214 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  184. Zacharek, S. J., Xiong, Y. & Shumway, S. D. Negative regulation of TSC1-TSC2 by mammalian D-type cyclins. Cancer Res. 65, 11354–11360 (2005).

    Article  CAS  PubMed  Google Scholar 

  185. Chandarlapaty, S. et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19, 58–71 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Zhang, J. et al. Inhibition of Rb phosphorylation leads to mTORC2-mediated activation of Akt. Mol. Cell 62, 929–942 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Olmez, I. et al. Combined c-Met/Trk inhibition overcomes resistance to CDK4/6 inhibitors in glioblastoma. Cancer Res. 78, 4360–4369 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Goldman, J. W. et al. A randomized phase III study of abemaciclib versus erlotinib in patients with stage IV non-small cell lung cancer with a detectable KRAS mutation who failed prior platinum-based therapy: JUNIPER. Front. Oncol. 10, 578756 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Kumarasamy, V., Vail, P., Nambiar, R., Witkiewicz, A. K. & Knudsen, E. S. Functional determinants of cell cycle plasticity and sensitivity to CDK4/6 inhibition. Cancer Res. 81, 1347–1360 (2021).

    Article  CAS  PubMed  Google Scholar 

  190. Knudsen, E. S. et al. Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer. Oncogene 38, 3355–3370 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Vilgelm, A. E. et al. MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21. Sci. Transl Med. 11, eaav7171 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. Fingar, D. C. et al. mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol. Cell. Biol. 24, 200–216 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Teh, J. L. F. et al. In vivo E2F reporting reveals efficacious schedules of MEK1/2-CDK4/6 targeting and mTOR-S6 resistance mechanisms. Cancer Discov. 8, 568–581 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Romano, G. et al. A pre-existing rare PIK3CAE545K subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling. Cancer Discov. 8, 556–567 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Michaloglou, C. et al. Combined inhibition of mTOR and CDK4/6 is required for optimal blockade of E2F function and long term growth inhibition in estrogen receptor positive breast cancer. Mol. Cancer Ther. 17, 908–920 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Olmez, I. et al. Combined CDK4/6 and mTOR inhibition is synergistic against glioblastoma via multiple mechanisms. Clin. Cancer Res. 23, 6958–6968 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Hart, L. S. et al. Preclinical therapeutic synergy of MEK1/2 and CDK4/6 inhibition in neuroblastoma. Clin. Cancer Res. 23, 1785–1796 (2017).

    Article  CAS  PubMed  Google Scholar 

  198. Ziemke, E. K. et al. Sensitivity of KRAS-mutant colorectal cancers to combination therapy that cotargets MEK and CDK4/6. Clin. Cancer Res. 22, 405–414 (2016).

    Article  CAS  PubMed  Google Scholar 

  199. Song, X. et al. Combined CDK4/6 and pan-mTOR inhibition is synergistic against intrahepatic cholangiocarcinoma. Clin. Cancer Res. 25, 403–413 (2019).

    Article  CAS  PubMed  Google Scholar 

  200. Zhou, J. et al. Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma. Gut 71, 665–675 (2021).

    Article  PubMed  Google Scholar 

  201. Yadav, V. et al. The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation. Mol. Cancer Ther. 13, 2253–2263 (2014).

    Article  CAS  PubMed  Google Scholar 

  202. Tao, Z. et al. Coadministration of trametinib and palbociclib radiosensitizes KRAS-mutant non-small cell lung cancers in vitro and in vivo. Clin. Cancer Res. 22, 122–133 (2016).

    Article  CAS  PubMed  Google Scholar 

  203. Sherr, C. J. A new cell-cycle target in cancer — inhibiting cyclin D–dependent kinases 4 and 6. N. Engl. J. Med. 375, 1920–1923 (2016).

    Article  CAS  PubMed  Google Scholar 

  204. Schaer, D. A. et al. The CDK4/6 inhibitor abemaciclib induces a T cell inflamed tumor microenvironment and enhances the efficacy of PD-L1 checkpoint blockade. Cell Rep. 22, 2978–2994 (2018).

    Article  CAS  PubMed  Google Scholar 

  205. Jerby-Arnon, L. et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell 175, 984–997.e24 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Uzhachenko, R. V. et al. Metabolic modulation by CDK4/6 inhibitor promotes chemokine-mediated recruitment of T cells into mammary tumors. Cell Rep. 35, 108944 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Litchfield, K. et al. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 184, 596–614.e14 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Yu, J. et al. Genetic aberrations in the CDK4 pathway are associated with innate resistance to PD-1 blockade in Chinese patients with non-cutaneous melanoma. Clin. Cancer Res. 25, 6511–6523 (2019).

    Article  CAS  PubMed  Google Scholar 

  209. Knudsen, E. S. et al. Targeting dual signalling pathways in concert with immune checkpoints for the treatment of pancreatic cancer. Gut 70, 127–138 (2021).

    Article  CAS  PubMed  Google Scholar 

  210. Whittle, J. R. et al. Dual targeting of CDK4/6 and BCL2 pathways augments tumor response in estrogen receptor-positive breast cancer. Clin. Cancer Res. 26, 4120–4134 (2020).

    Article  CAS  PubMed  Google Scholar 

  211. Lelliott, E. J. et al. CDK4/6 inhibition promotes anti-tumor immunity through the induction of T cell memory. Cancer Discov. 11, 2582–2601 (2021).

    Article  CAS  PubMed  Google Scholar 

  212. Heckler, M. et al. Inhibition of CDK4/6 promotes CD8 T-cell memory formation. Cancer Discov. 11, 2564–2581 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Tan, A. R. et al. Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol. 20, 1587–1601 (2019).

    Article  CAS  PubMed  Google Scholar 

  214. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT04799249 (2022).

  215. Gonzalez-Gualda, E. et al. Galacto-conjugation of navitoclax as an efficient strategy to increase senolytic specificity and reduce platelet toxicity. Aging Cell 19, e13142 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Gadsden, N. J. et al. Palbociclib renders human papilloma virus-negative head and neck squamous cell carcinoma vulnerable to the senolytic agent navitoclax. Mol. Cancer Res. 19, 862–873 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Ji, Y. et al. Use of ratiometrically designed nanocarrier targeting CDK4/6 and autophagy pathways for effective pancreatic cancer treatment. Nat. Commun. 11, 4249 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT03900884 (2020).

  219. Brown, N. E. et al. Cyclin D1 activity regulates autophagy and senescence in the mammary epithelium. Cancer Res. 72, 6477–6489 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Vijayaraghavan, S. et al. CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers. Nat. Commun. 8, 15916 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Fassl, A. et al. Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition. Sci. Adv. 6, eabb2210 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Franco, J., Balaji, U., Freinkman, E., Witkiewicz, A. K. & Knudsen, E. S. Metabolic reprogramming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities. Cell Rep. 14, 979–990 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Tarrado-Castellarnau, M. et al. De novo MYC addiction as an adaptive response of cancer cells to CDK4/6 inhibition. Mol. Syst. Biol. 13, 940 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  224. Ge, J. Y. et al. Acquired resistance to combined BET and CDK4/6 inhibition in triple-negative breast cancer. Nat. Commun. 11, 2350 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Liao, S., Maertens, O., Cichowski, K. & Elledge, S. J. Genetic modifiers of the BRD4-NUT dependency of NUT midline carcinoma uncovers a synergism between BETis and CDK4/6is. Genes Dev. 32, 1188–1200 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. McClendon, A. K. et al. CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle 11, 2747–2755 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Roberts, P. J. et al. Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J. Natl Cancer Inst. 104, 476–487 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Johnson, S. M. et al. Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. J. Clin. Invest. 120, 2528–2536 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Hashizume, R. et al. Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth. Neuro Oncol. 18, 1519–1528 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Barton, K. L. et al. PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma. PLoS ONE 8, e77639 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Naz, S. et al. Abemaciclib, a selective CDK4/6 inhibitor, enhances the radiosensitivity of non–small cell lung cancer in vitro and in vivo. Clin. Cancer Res. 24, 3994–4005 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Weiss, J. M. et al. Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial. Ann. Oncol. 30, 1613–1621 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Wei, L. et al. Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice. J. Clin. Invest. 126, 4076–4087 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  234. Purba, T. S. et al. CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane-induced alopecia. EMBO Mol. Med. 11, e11031 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Pabla, N. et al. Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions. Proc. Natl Acad. Sci. USA 112, 5231–5236 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. DiRocco, D. P. et al. CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury. Am. J. Physiol. Ren. Physiol. 306, F379–F388 (2014).

    Article  CAS  Google Scholar 

  237. Mayer, E. L. et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 22, 212–222 (2021).

    Article  CAS  PubMed  Google Scholar 

  238. Johnston, S. R. D. et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer (monarchE). J. Clin. Oncol. 38, 3987–3998 (2020). This randomized phase III trial demonstrates that the addition of abemaciclib therapy to endocrine therapy increases disease-free survival for patients with high-risk, HR-positive, HER2-negative breast cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Loibl, S. et al. Phase III study of palbociclib combined with endocrine therapy (ET) in patients with hormone-receptor-positive (HR+), HER2-negative primary breast cancer and with high relapse risk after neoadjuvant chemotherapy (NACT): first results from PENELOPE-B. Cancer Res. 81, GS1–GS02 (2021).

    Article  Google Scholar 

  240. Zhao, B. & Burgess, K. PROTACs suppression of CDK4/6, crucial kinases for cell cycle regulation in cancer. Chem. Commun. 55, 2704–2707 (2019).

    Article  CAS  Google Scholar 

  241. Brand, M. et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem. Biol. 26, 300–306.e9 (2019).

    Article  CAS  PubMed  Google Scholar 

  242. Jiang, B. et al. Development of dual and selective degraders of cyclin-dependent kinases 4 and 6. Angew. Chem. Int. Ed. 58, 6321–6326 (2019).

    Article  CAS  Google Scholar 

  243. Anderson, N. A. et al. Selective CDK6 degradation mediated by cereblon, VHL, and novel IAP-recruiting PROTACs. Bioorg. Med. Chem. Lett. 30, 127106 (2020).

    Article  CAS  PubMed  Google Scholar 

  244. Rana, S. et al. Selective degradation of CDK6 by a palbociclib based PROTAC. Bioorg. Med. Chem. Lett. 29, 1375–1379 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  245. De Dominici, M. et al. Selective inhibition of Ph-positive ALL cell growth through kinase-dependent and -independent effects by CDK6-specific PROTACs. Blood 135, 1560–1573 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  246. Hortobagyi, G. N. et al. in San Antonio Breast Cancer Symposium (SABCS, 2021).

  247. Alvarez-Fernandez, M. & Malumbres, M. Mechanisms of sensitivity and resistance to CDK4/6 inhibition. Cancer Cell 37, 514–529 (2020).

    Article  CAS  PubMed  Google Scholar 

  248. Condorelli, R. et al. Polyclonal RB1 mutations and acquired resistance to CDK 4/6 inhibitors in patients with metastatic breast cancer. Ann. Oncol. 29, 640–645 (2017).

    Article  Google Scholar 

  249. O’Leary, B. et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 8, 1390–1403 (2018). This circulating biomarker analysis of the PALOMA-3 study describes mutational profiling of HR-positive breast cancers treated with endocrine therapy with or without palbociclib therapy, performed using paired blood samples taken at the baseline and at disease progression.

    Article  PubMed  PubMed Central  Google Scholar 

  250. Costa, C. et al. PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kalpha inhibitors in breast cancer. Cancer Discov. 10, 72–85 (2020).

    Article  CAS  PubMed  Google Scholar 

  251. Wander, S. A. et al. The genomic landscape of intrinsic and acquired resistance to cyclin-dependent kinase 4/6 inhibitors in patients with hormone receptor–positive metastatic breast cancer. Cancer Discov. 10, 1174–1193 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Turner, N. C. et al. Cyclin E1 expression and palbociclib efficacy in previously treated hormone receptor-positive metastatic breast cancer. J. Clin. Oncol. 37, 1169–1178 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Choi, Y. J. et al. Development of a selective CDK2-E inhibitor in CCNE driven cancers. Cancer Res. 81, 1279 (2021).

    Article  Google Scholar 

  254. Sabnis, R. W. Novel CDK2 inhibitors for treating cancer. ACS Med. Chem. Lett. 11, 2346–2347 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Freeman-Cook, K. et al. Expanding control of the tumor cell cycle with a CDK2/4/6 inhibitor. Cancer Cell 39, 1404–1421.e11 (2021).

    Article  CAS  PubMed  Google Scholar 

  256. Yang, C. et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene 36, 2255–2264 (2017).

    Article  CAS  PubMed  Google Scholar 

  257. Cornell, L., Wander, S. A., Visal, T., Wagle, N. & Shapiro, G. I. MicroRNA-mediated suppression of the TGF-β pathway confers transmissible and reversible CDK4/6 inhibitor resistance. Cell Rep. 26, 2667–2680.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Li, Q. et al. INK4 tumor suppressor proteins mediate resistance to CDK4/6 kinase inhibitors. Cancer Discov. 12, 356–371 (2021). This study demonstrates that CDK6 can induce CDK4/6 inhibitor resistance by inducing expression of INK4C, providing a mechanistic hypothesis to explain prior studies implicating CDK6 as a driver of resistance.

    Article  PubMed  Google Scholar 

  259. Glover-Cutter, K. et al. TFIIH-associated Cdk7 kinase functions in phosphorylation of C-terminal domain Ser7 residues, promoter-proximal pausing, and termination by RNA polymerase II. Mol. Cell. Biol. 29, 5455–5464 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Larochelle, S., Pandur, J., Fisher, R. P., Salz, H. K. & Suter, B. Cdk7 is essential for mitosis and for in vivo Cdk-activating kinase activity. Genes Dev. 12, 370–381 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Coombes, C. et al. in San Antonio Breast Cancer Symposium (SABCS, 2021).

  262. Llanos, S. et al. Lysosomal trapping of palbociclib and its functional implications. Oncogene 38, 3886–3902 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Sudhan, D. et al. in San Antonio Breast Cancer Symposium (SABCS, 2021).

Download references

Acknowledgements

S.G. is a Snow fellow of the Snow Medical Research Foundation. S.G. receives research funding support from the National Health and Medical Research Council of Australia (Investigator Grant GNT1177357), the US National Institutes of Health (P50 CA165962-06A1) and The Mark Foundation for Cancer Research (ASPIRE award). J.J.Z. acknowledges funding from the Breast Cancer Research Foundation (BCRF-21-179), the US Department of Defense Congressionally Directed Medical Research Programs (W81XWH-18-1-0491) and the National Institutes of Health National Cancer Institute (CA168504, CA165962, CA203655 and R35 CA210057).

Author information

Author notes

  1. These authors contributed equally: Shom Goel, Johann S. Bergholz.

Authors and Affiliations

  1. Peter MacCallum Cancer Centre, Melbourne, VIC, Australia

    Shom Goel

  2. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia

    Shom Goel

  3. Dana-Farber Cancer Institute, Boston, MA, USA

    Johann S. Bergholz & Jean J. Zhao

  4. Harvard Medical School, Boston, MA, USA

    Johann S. Bergholz & Jean J. Zhao

  5. Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Johann S. Bergholz & Jean J. Zhao

Authors
  1. Shom Goel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Johann S. Bergholz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jean J. Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors contributed equally to the conception and direction of the Review. S.G. and J.S.B. contributed equally to all aspects of the Review. J.J.Z. edited the manuscript for content, clarity and accuracy.

Corresponding authors

Correspondence to Shom Goel or Jean J. Zhao.

Ethics declarations

Competing interests

S.G. has received funding to support laboratory research from Eli Lilly and G1 Therapeutics. S.G. has served as a paid adviser to Eli Lilly, G1 Therapeutics and Pfizer. J.S.B. is a scientific consultant for Geode Therapeutics. J.J.Z. was a co-founder of and is board director of Crimson Biotech and Geode Therapeutics.

Peer review

Peer review information

Nature Reviews Cancer thanks Stacy Blain, Marcos Malumbres and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Glossary

Mitogenic signals

Signals arising from small extracellular proteins or peptides that induce a cell to begin cell division.

Interphase

The portion of the cell cycle including G1, S and G2 phases, but excluding M phase; interphase begins at the end of one mitotic division and ends at the beginning of the next mitotic division.

Endocrine therapy

A therapy that alters the effect of sex steroid hormones in cancer cells; in breast cancer, endocrine therapy is used to block the effect of oestrogen in hormone receptor-positive breast tumours.

Replication origin licensing

The initial step for DNA replication initiation during late G1–early S phase, during which the prereplicative complex is recruited to replication origins.

Lymphokines

A type of cytokine (that is, a small secreted protein with autocrine, paracrine and/or endocrine functions) produced and secreted by lymphocytes.

Thrombocytopenia

Low blood count of platelets (thrombocytes), a type of blood cell important for clotting.

Homologous recombination

The exchange of genetic material between homologous chromosomes; an important mechanism used by cells to repair deleterious DNA damages such as double-strand breaks and collapsed replication forks.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Goel, S., Bergholz, J.S. & Zhao, J.J. Targeting CDK4 and CDK6 in cancer. Nat Rev Cancer 22, 356–372 (2022). https://doi.org/10.1038/s41568-022-00456-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41568-022-00456-3

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing