1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Cancer Biology
  4. Volume 4, 2020
  5. Article

Annual Review of Cancer Biology

Volume 4, 2020

Nongenetic Mechanisms of Drug Resistance in Melanoma

Abstract

Resistance to targeted and immune-based therapies limits cures in patients with metastatic melanoma. A growing number of reports have identified nongenetic primary resistance mechanisms including intrinsic microenvironment- and lineage plasticity–mediated processes serving critical functions in the persistence of disease throughout therapy. There is a temporally shifting spectrum of cellular identities fluidly occupied by therapy-persisting melanoma cells responsible for driving therapeutic resistance and metastasis. The key epigenetic, metabolic, and phenotypic reprogramming events requisite for the manifestation and maintenance of so-called persister melanoma populations remain poorly understood and underscore the need to comprehensively investigate actionable vulnerabilities. Here we attempt to integrate the field's observations on nongenetic mechanisms of drug resistance in melanoma. We postulate that the future design of therapeutic strategies specifically addressing therapy-persisting subpopulations of melanoma will improve the curative potential of therapy for patients with metastatic disease.

Keyword(s): dedifferentiation, metastasis, neural crest stem cell, plasticity, therapy resistance
Loading

Article metrics loading...

/content/journals/10.1146/annurev-cancerbio-030419-033533
2020-03-04
2024-04-23
Loading full text...

Full text loading...

/deliver/fulltext/cancerbio/4/1/annurev-cancerbio-030419-033533.html?itemId=/content/journals/10.1146/annurev-cancerbio-030419-033533&mimeType=html&fmt=ahah

Literature Cited

  1. Abel EV, Basile KJ, Kugel CH III, Witkiewicz AK, Le K et al. 2013. Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. J. Clin. Investig 123:2155–68
     [Google Scholar]
  2. Almeida FV, Douglass SM, Fane ME, Weeraratna AT 2019. Bad company: microenvironmentally mediated resistance to targeted therapy in melanoma. Pigment Cell Melanoma Res 32:237–47
     [Google Scholar]
  3. Am. Cancer Soc 2019. Cancer Facts and Figures 2019 Atlanta, GA: Am. Cancer Soc.
  4. Anderberg C, Li H, Fredriksson L, Andrae J, Betsholtz C et al. 2009. Paracrine signaling by platelet-derived growth factor-CC promotes tumor growth by recruitment of cancer-associated fibroblasts. Cancer Res 69:369–78
     [Google Scholar]
  5. Atay C, Kwak T, Lavilla-Alonso S, Donthireddy L, Richards A et al. 2019. BRAF targeting sensitizes resistant melanoma to cytotoxic T cells. Clin. Cancer Res. 25:2783–94
     [Google Scholar]
  6. Bai X, Fisher DE, Flaherty KT 2019. Cell-state dynamics and therapeutic resistance in melanoma from the perspective of MITF and IFNγ pathways. Nat. Rev. Clin. Oncol. 16:9549–62
     [Google Scholar]
  7. Berking C, Takemoto R, Satyamoorthy K, Elenitsas R, Herlyn M 2001a. Basic fibroblast growth factor and ultraviolet B transform melanocytes in human skin. Am. J. Pathol. 158:943–53
     [Google Scholar]
  8. Berking C, Takemoto R, Schaider H, Showe L, Satyamoorthy K et al. 2001b. Transforming growth factor-β1 increases survival of human melanoma through stroma remodeling. Cancer Res 61:8306–16
     [Google Scholar]
  9. Bonnet D, Dick JE. 1997. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3:730–77
     [Google Scholar]
  10. Boshuizen J, Koopman LA, Krijgsman O, Shahrabi A, Van Den Heuvel EG et al. 2018. Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Nat. Med. 24:203–12
     [Google Scholar]
  11. Botton T, Yeh I, Nelson T, Vemula SS, Sparatta A et al. 2013. Recurrent BRAF kinase fusions in melanocytic tumors offer an opportunity for targeted therapy. Pigment Cell Melanoma Res 26:845–51
     [Google Scholar]
  12. Buszczak M, Signer RA, Morrison SJ 2014. Cellular differences in protein synthesis regulate tissue homeostasis. Cell 159:242–51
     [Google Scholar]
  13. Callahan MK, Masters G, Pratilas CA, Ariyan C, Katz J et al. 2014. Paradoxical activation of T cells via augmented ERK signaling mediated by a RAF inhibitor. Cancer Immunol. Res. 2:70–79
     [Google Scholar]
  14. Caporali S, Alvino E, Lacal PM, Levati L, Giurato G et al. 2016. Targeting the PI3K/AKT/mTOR pathway overcomes the stimulating effect of dabrafenib on the invasive behavior of melanoma cells with acquired resistance to the BRAF inhibitor. Int. J. Oncol. 49:1164–74
     [Google Scholar]
  15. Caramel J, Papadogeorgakis E, Hill L, Browne GJ, Richard G et al. 2013. A switch in the expression of embryonic EMT-inducers drives the development of malignant melanoma. Cancer Cell 24:466–80
     [Google Scholar]
  16. Carlino MS, Long GV, Schadendorf D, Robert C, Ribas A et al. 2018. Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: a randomised clinical trial. Eur. J. Cancer 101:236–243
     [Google Scholar]
  17. Carreira S, Goodall J, Denat L, Rodriguez M, Nuciforo P et al. 2006. Mitf regulation of Dia1 controls melanoma proliferation and invasiveness. Genes Dev 20:3426–39
     [Google Scholar]
  18. Cho HI, Lee YR, Celis E 2011. Interferon γ limits the effectiveness of melanoma peptide vaccines. Blood 117:135–44
     [Google Scholar]
  19. Colo GP, Hernandez-Varas P, Lock J, Bartolome RA, Arellano-Sanchez N et al. 2012. Focal adhesion disassembly is regulated by a RIAM to MEK-1 pathway. J. Cell Sci. 125:5338–52
     [Google Scholar]
  20. Deng W, Gopal YN, Scott A, Chen G, Woodman SE, Davies MA 2012. Role and therapeutic potential of PI3K-mTOR signaling in de novo resistance to BRAF inhibition. Pigment Cell Melanoma Res 25:248–58
     [Google Scholar]
  21. Dumaz N, Hayward R, Martin J, Ogilvie L, Hedley D et al. 2006. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res 66:9483–91
     [Google Scholar]
  22. Dummer R, Ascierto PA, Gogas HJ, Arance A, Mandala M et al. 2018. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 19:1315–27
     [Google Scholar]
  23. Elias EG, Hasskamp JH, Sharma BK 2010. Cytokines and growth factors expressed by human cutaneous melanoma. Cancers 2:794–808
     [Google Scholar]
  24. Fallahi-Sichani M, Becker V, Izar B, Baker GJ, Lin JR et al. 2017. Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state. Mol. Syst. Biol. 13:905
     [Google Scholar]
  25. Falletta P, Sanchez-Del-Campo L, Chauhan J, Effern M, Kenyon A et al. 2017. Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma. Genes Dev 31:18–33
     [Google Scholar]
  26. Fang D, Setaluri V. 1999. Role of microphthalmia transcription factor in regulation of melanocyte differentiation marker TRP-1. Biochem. Biophys. Res. Commun. 256:657–63
     [Google Scholar]
  27. Fidler IJ. 2003. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat. Rev. Cancer 3:453–58
     [Google Scholar]
  28. Fischer GM, Jalali A, Kircher DA, Lee WC, McQuade JL et al. 2019. Molecular profiling reveals unique immune and metabolic features of melanoma brain metastases. Cancer Discov 9:628–45
     [Google Scholar]
  29. Flach EH, Rebecca VW, Herlyn M, Smalley KS, Anderson AR 2011. Fibroblasts contribute to melanoma tumor growth and drug resistance. Mol. Pharm. 8:2039–49
     [Google Scholar]
  30. Frame MC, Serrels A. 2015. FAK to the rescue: activated stroma promotes a “safe haven” for BRAF-mutant melanoma cells by inducing FAK signaling. Cancer Cell 27:429–31
     [Google Scholar]
  31. Girotti MR, Pedersen M, Sanchez-Laorden B, Viros A, Turajlic S et al. 2013. Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer Discov 3:158–67
     [Google Scholar]
  32. Gopal YN, Rizos H, Chen G, Deng W, Frederick DT et al. 2014. Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1α and oxidative phosphorylation in melanoma. Cancer Res 74:7037–47
     [Google Scholar]
  33. Hamid O, Robert C, Daud A, Hodi FS, Hwu WJ et al. 2019. Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Ann. Oncol. 30:582–88
     [Google Scholar]
  34. Han S, Ren Y, He W, Liu H, Zhi Z et al. 2018. ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma. Nat. Commun. 9:28
     [Google Scholar]
  35. Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE 1998. MAP kinase links the transcription factor Microphthalmia to c-Kit signalling in melanocytes. Nature 391:298–301
     [Google Scholar]
  36. Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B et al. 2015. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin β1/FAK signaling. Cancer Cell 27:574–88
     [Google Scholar]
  37. Hoek KS, Eichhoff OM, Schlegel NC, Dobbeling U, Kobert N et al. 2008. In vivo switching of human melanoma cells between proliferative and invasive states. Cancer Res 68:650–56
     [Google Scholar]
  38. Hoek KS, Goding CR. 2010. Cancer stem cells versus phenotype-switching in melanoma. Pigment Cell Melanoma Res 23:746–59
     [Google Scholar]
  39. Hoek KS, Schlegel NC, Brafford P, Sucker A, Ugurel S et al. 2006. Metastatic potential of melanomas defined by specific gene expression profiles with no BRAF signature. Pigment Cell Res 19:290–302
     [Google Scholar]
  40. Huang S. 2013. Genetic and non-genetic instability in tumor progression: link between the fitness landscape and the epigenetic landscape of cancer cells. Cancer Metastasis Rev 32:423–48
     [Google Scholar]
  41. Kaur A, Webster MR, Marchbank K, Behera R, Ndoye A et al. 2016. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532:250–54
     [Google Scholar]
  42. Kim G, McKee AE, Ning YM, Hazarika M, Theoret M et al. 2014. FDA approval summary: vemurafenib for treatment of unresectable or metastatic melanoma with the BRAFV600E mutation. Clin. Cancer Res. 20:4994–5000
     [Google Scholar]
  43. Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA et al. 2014. A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov 4:816–27
     [Google Scholar]
  44. Krepler C, Sproesser K, Brafford P, Beqiri M, Garman B et al. 2017. A comprehensive patient-derived xenograft collection representing the heterogeneity of melanoma. Cell Rep 21:1953–67
     [Google Scholar]
  45. Kugel CH 3rd, Douglass SM, Webster MR, Kaur A, Liu Q et al. 2018. Age correlates with response to anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations. Clin. Cancer Res. 24:5347–56
     [Google Scholar]
  46. Leclerc J, Garandeau D, Pandiani C, Gaudel C, Bille K et al. 2019. Lysosomal acid ceramidase ASAH1 controls the transition between invasive and proliferative phenotype in melanoma cells. Oncogene 38:1282–95
     [Google Scholar]
  47. Lemech C, Infante J, Arkenau HT 2013. Combination molecularly targeted drug therapy in metastatic melanoma: progress to date. Drugs 73:767–77
     [Google Scholar]
  48. Levati L, Ruffini F, Muzi A, Umezawa K, Graziani G et al. 2011. Placenta growth factor induces melanoma resistance to temozolomide through a mechanism that involves the activation of the transcription factor NF-κB. Int. J. Oncol. 38:241–47
     [Google Scholar]
  49. Li Z, Zhang LJ, Zhang HR, Tian GF, Tian J et al. 2014. Tumor-derived transforming growth factor-β is critical for tumor progression and evasion from immune surveillance. Asian Pac J. Cancer Prev. 15:5181–86
     [Google Scholar]
  50. Long GV, Eroglu Z, Infante J, Patel S, Daud A et al. 2018. Long-term outcomes in patients with BRAF V600-mutant metastatic melanoma who received dabrafenib combined with trametinib. J. Clin. Oncol. 36:667–73
     [Google Scholar]
  51. Long JE, Wongchenko MJ, Nickles D, Chung W-J, Wang B-E et al. 2019. Therapeutic resistance and susceptibility is shaped by cooperative multi-compartment tumor adaptation. Cell Death Differ 26:2416–29
     [Google Scholar]
  52. Ma XH, Piao SF, Dey S, McAfee Q, Karakousis G et al. 2014. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma. J. Clin. Investig. 124:1406–17
     [Google Scholar]
  53. Mehta A, Kim YJ, Robert L, Tsoi J, Comin-Anduix B et al. 2018. Immunotherapy resistance by inflammation-induced dedifferentiation. Cancer Discov 8:935–43
     [Google Scholar]
  54. Menter DG, Herrmann JL, Nicolson GL 1995. The role of trophic factors and autocrine/paracrine growth factors in brain metastasis. Clin. Exp. Metastasis 13:67–88
     [Google Scholar]
  55. Moellering RE, Black KC, Krishnamurty C, Baggett BK, Stafford P et al. 2008. Acid treatment of melanoma cells selects for invasive phenotypes. Clin. Exp. Metastasis 25:411–25
     [Google Scholar]
  56. Muller J, Krijgsman O, Tsoi J, Robert L, Hugo W et al. 2014. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma. Nat. Commun. 5:5712
     [Google Scholar]
  57. Nazarian R, Shi H, Wang Q, Kong X, Koya RC et al. 2010. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–77
     [Google Scholar]
  58. Ndoye A, Budina-Kolomets A, Kugel CH 3rd, Webster MR, Kaur A et al. 2017. ATG5 mediates a positive feedback loop between Wnt signaling and autophagy in melanoma. Cancer Res 77:5873–85
     [Google Scholar]
  59. Ojha R, Leli NM, Onorati A, Piao S, Verginadis II et al. 2019. ER translocation of the MAPK pathway drives therapy resistance in BRAF-mutant melanoma. Cancer Discov 9:396–415
     [Google Scholar]
  60. Pagani E, Ruffini F, Antonini Cappellini GC, Scoppola A, Fortes C et al. 2016. Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness. Int. J. Oncol. 48:1581–89
     [Google Scholar]
  61. Paraiso KH, Xiang Y, Rebecca VW, Abel EV, Chen YA et al. 2011. PTEN loss confers BRAF inhibitor resistance to melanoma cells through the suppression of BIM expression. Cancer Res 71:2750–60
     [Google Scholar]
  62. Peng W, Chen JQ, Liu C, Malu S, Creasy C et al. 2016. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov 6:202–16
     [Google Scholar]
  63. Perego M, Maurer M, Wang JX, Shaffer S, Muller AC et al. 2018. A slow-cycling subpopulation of melanoma cells with highly invasive properties. Oncogene 37:302–12
     [Google Scholar]
  64. Perotti V, Baldassari P, Molla A, Nicolini G, Bersani I et al. 2019. An actionable axis linking NFATc2 to EZH2 controls the EMT-like program of melanoma cells. Oncogene 38:4384–96
     [Google Scholar]
  65. Postow MA, Callahan MK, Wolchok JD 2015. Immune checkpoint blockade in cancer therapy. J. Clin. Oncol. 33:1974–82
     [Google Scholar]
  66. Queirolo P, Picasso V, Spagnolo F 2015. Combined BRAF and MEK inhibition for the treatment of BRAF-mutated metastatic melanoma. Cancer Treat. Rev. 41:519–26
     [Google Scholar]
  67. Rambow F, Rogiers A, Marin-Bejar O, Aibar S, Femel J et al. 2018. Toward minimal residual disease-directed therapy in melanoma. Cell 174:843–55.e19
     [Google Scholar]
  68. Rebecca VW, Alicea GM, Paraiso KH, Lawrence H, Gibney GT, Smalley KS 2014a. Vertical inhibition of the MAPK pathway enhances therapeutic responses in NRAS-mutant melanoma. Pigment Cell Melanoma Res 27:1154–58
     [Google Scholar]
  69. Rebecca VW, Massaro RR, Fedorenko IV, Sondak VK, Anderson AR et al. 2014b. Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma. Pigment Cell Melanoma Res 27:465–78
     [Google Scholar]
  70. Rebecca VW, Nicastri MC, McLaughlin N, Fennelly C, McAfee Q et al. 2017. A unified approach to targeting the lysosome's degradative and growth signaling roles. Cancer Discov 7:1266–83
     [Google Scholar]
  71. Rebecca VW, Smalley KS. 2011. Tumor heterogeneity and strategies to overcome kinase inhibitor resistance in cancer: lessons from melanoma. Expert Opin. Investig. Drugs 20:137–40
     [Google Scholar]
  72. Rebecca VW, Wood E, Fedorenko IV, Paraiso KH, Haarberg HE et al. 2014c. Evaluating melanoma drug response and therapeutic escape with quantitative proteomics. Mol. Cell. Proteom. 13:1844–54
     [Google Scholar]
  73. Reya T, Morrison SJ, Clarke MF, Weissman IL 2001. Stem cells, cancer, and cancer stem cells. Nature 414:105–11
     [Google Scholar]
  74. Ribas A, Wolchok JD. 2018. Cancer immunotherapy using checkpoint blockade. Science 359:1350–55
     [Google Scholar]
  75. Richard G, Dalle S, Monet MA, Ligier M, Boespflug A et al. 2016. ZEB1-mediated melanoma cell plasticity enhances resistance to MAPK inhibitors. EMBO Mol. Med. 8:1143–61
     [Google Scholar]
  76. Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA et al. 2010. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141:583–94
     [Google Scholar]
  77. Roesch A, Paschen A, Landsberg J, Helfrich I, Becker JC, Schadendorf D 2016. Phenotypic tumour cell plasticity as a resistance mechanism and therapeutic target in melanoma. Eur. J. Cancer 59:109–12
     [Google Scholar]
  78. Roesch A, Vultur A, Bogeski I, Wang H, Zimmermann KM et al. 2013. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells. Cancer Cell 23:811–25
     [Google Scholar]
  79. Rohrbeck L, Gong JN, Lee EF, Kueh AJ, Behren A et al. 2016. Hepatocyte growth factor renders BRAF mutant human melanoma cell lines resistant to PLX4032 by downregulating the pro-apoptotic BH3-only proteins PUMA and BIM. Cell Death Differ 23:2054–62
     [Google Scholar]
  80. Ruiter D, Bogenrieder T, Elder D, Herlyn M 2002. Melanoma-stroma interactions: structural and functional aspects. Lancet Oncol 3:35–43
     [Google Scholar]
  81. Saei A, Eichhorn PJA. 2018. Ubiquitination and adaptive responses to BRAF inhibitors in melanoma. Mol. Cell. Oncol. 5:e1497862
     [Google Scholar]
  82. Schachter J, Ribas A, Long GV, Arance A, Grob JJ et al. 2017. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet 390:1853–62
     [Google Scholar]
  83. Schadendorf D, Long GV, Stroiakovski D, Karaszewska B, Hauschild A et al. 2017. Three-year pooled analysis of factors associated with clinical outcomes across dabrafenib and trametinib combination therapy phase 3 randomised trials. Eur. J. Cancer 82:45–55
     [Google Scholar]
  84. Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM et al. 2008. Identification of cells initiating human melanomas. Nature 451:345–49
     [Google Scholar]
  85. Shaffer SM, Dunagin MC, Torborg SR, Torre EA, Emert B et al. 2017. Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. Nature 546:431–35
     [Google Scholar]
  86. Sharma P, Wagner K, Wolchok JD, Allison JP 2011. Novel cancer immunotherapy agents with survival benefit: recent successes and next steps. Nat. Rev. Cancer 11:805–12
     [Google Scholar]
  87. Shih IM, Herlyn M. 1993. Role of growth factors and their receptors in the development and progression of melanoma. J. Investig. Dermatol. 100:S196–203
     [Google Scholar]
  88. Shih IM, Herlyn M. 1994. Autocrine and paracrine roles for growth factors in melanoma. In Vivo 8:113–23
     [Google Scholar]
  89. Smith MP, Brunton H, Rowling EJ, Ferguson J, Arozarena I et al. 2016. Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy. Cancer Cell 29:270–84
     [Google Scholar]
  90. Smith MP, Rana S, Ferguson J, Rowling EJ, Flaherty KT et al. 2019. A PAX3/BRN2 rheostat controls the dynamics of BRAF mediated MITF regulation in MITFhigh /AXLlow melanoma. Pigment Cell Melanoma Res 32:280–91
     [Google Scholar]
  91. Somasundaram R, Zhang G, Fukunaga-Kalabis M, Perego M, Krepler C et al. 2017. Tumor-associated B-cells induce tumor heterogeneity and therapy resistance. Nat. Commun. 8:607
     [Google Scholar]
  92. Song C, Piva M, Sun L, Hong A, Moriceau G et al. 2017. Recurrent tumor cell-intrinsic and -extrinsic alterations during MAPKi-induced melanoma regression and early adaptation. Cancer Discov 7:1248–65
     [Google Scholar]
  93. Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian ZR et al. 2012. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 487:500–4
     [Google Scholar]
  94. Sun C, Wang L, Huang S, Heynen GJ, Prahallad A et al. 2014. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508:118–22
     [Google Scholar]
  95. Sweetlove M, Wrightson E, Kolekar S, Rewcastle GW, Baguley BC et al. 2015. Inhibitors of pan-PI3K signaling synergize with BRAF or MEK inhibitors to prevent BRAF-mutant melanoma cell growth. Front. Oncol. 5:135
     [Google Scholar]
  96. Teh JLF, Cheng PF, Purwin TJ, Nikbakht N, Patel P et al. 2018. In vivo E2F reporting reveals efficacious schedules of MEK1/2-CDK4/6 targeting and mTOR-S6 resistance mechanisms. Cancer Discov 8:568–81
     [Google Scholar]
  97. Tirosh I, Izar B, Prakadan SM, Wadsworth MH II, Treacy D et al. 2016. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 352:189–96
     [Google Scholar]
  98. Verfaillie A, Imrichova H, Atak ZK, Dewaele M, Rambow F et al. 2015. Decoding the regulatory landscape of melanoma reveals TEADS as regulators of the invasive cell state. Nat. Commun. 6:6683
     [Google Scholar]
  99. Vido MJ, Le K, Hartsough EJ, Aplin AE 2018. BRAF splice variant resistance to RAF inhibitor requires enhanced MEK association. Cell Rep 25:1501–10.e3
     [Google Scholar]
  100. Villanueva J, Herlyn M. 2008. Melanoma and the tumor microenvironment. Curr. Oncol. Rep. 10:439–46
     [Google Scholar]
  101. Villanueva J, Infante JR, Krepler C, Reyes-Uribe P, Samanta M et al. 2013. Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep 4:1090–99
     [Google Scholar]
  102. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M et al. 2010. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18:683–95
     [Google Scholar]
  103. Vlckova K, Vachtenheim J, Reda J, Horak P, Ondrusova L 2018. Inducibly decreased MITF levels do not affect proliferation and phenotype switching but reduce differentiation of melanoma cells. J. Cell. Mol. Med. 22:2240–51
     [Google Scholar]
  104. Vultur A, Villanueva J, Krepler C, Rajan G, Chen Q et al. 2014. MEK inhibition affects STAT3 signaling and invasion in human melanoma cell lines. Oncogene 33:1850–61
     [Google Scholar]
  105. Wang T, Feldman GM, Herlyn M, Kaufman RE 2015a. The macrophage: Switches from a passenger to a driver during anticancer therapy. Oncoimmunology 4:e1052929
     [Google Scholar]
  106. Wang T, Xiao M, Ge Y, Krepler C, Belser E et al. 2015b. BRAF inhibition stimulates melanoma-associated macrophages to drive tumor growth. Clin. Cancer Res. 21:1652–64
     [Google Scholar]
  107. Welsh SJ, Rizos H, Scolyer RA, Long GV 2016. Resistance to combination BRAF and MEK inhibition in metastatic melanoma: Where to next. ? Eur. J. Cancer 62:76–85
     [Google Scholar]
  108. Willenberg A, Saalbach A, Simon JC, Anderegg U 2012. Melanoma cells control HA synthesis in peritumoral fibroblasts via PDGF-AA and PDGF-CC: impact on melanoma cell proliferation. J. Investig. Dermatol. 132:385–93
     [Google Scholar]
  109. Yasumoto K, Yokoyama K, Shibata K, Tomita Y, Shibahara S 1994. Microphthalmia-associated transcription factor as a regulator for melanocyte-specific transcription of the human tyrosinase gene. Mol. Cell Biol. 14:8058–70
     [Google Scholar]
  110. Zabierowski SE, Herlyn M. 2008a. Learning the ABCs of melanoma-initiating cells. Cancer Cell 13:185–87
     [Google Scholar]
  111. Zabierowski SE, Herlyn M. 2008b. Melanoma stem cells: the dark seed of melanoma. J. Clin. Oncol. 26:2890–94
     [Google Scholar]
  112. Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W et al. 2016. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375:819–29
     [Google Scholar]
  113. Zhang G, Frederick DT, Wu L, Wei Z, Krepler C et al. 2016. Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. J. Clin. Investig. 126:1834–56
     [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030419-033533
Loading
Nongenetic Mechanisms of Drug Resistance in Melanoma
Annual Review of Cancer Biology 4, 315 (2020); https://doi.org/10.1146/annurev-cancerbio-030419-033533
/content/journals/10.1146/annurev-cancerbio-030419-033533
/content/journals/10.1146/annurev-cancerbio-030419-033533
Loading

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error