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Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression

Oncogene volume 39, pages 4077–4091 (2020)Cite this article

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Abstract

Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting tumor heterogeneity. We have performed multi-omic profiling of the kinome in bladder cancer patients with the goal of identify therapeutic targets. Our analyses revealed amplification, overexpression, and elevated kinase activity of P21 (RAC1) activated kinase 4 (PAK4) in a subset of Bladder cancer (BLCA). Using bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, we observed that a PAK4 inhibitor was effective in curtailing growth of BLCA cells. Transcriptomic analyses identified elevated expression of another kinase, protein tyrosine kinase 6 (PTK6), upon treatment with a PAK4 inhibitor and RNA interference of PAK4. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared with either drug alone. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients with amplified and/or overexpressed PAK4 in their tumors. Our results also indicate that combined inhibition of PAK4 and PTK6 may overcome resistance to PAK4. These observations warrant clinical investigations with selected BLCA patients.

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Fig. 1: Multi-platform kinome analysis of 24 MIBCs and their matched normal tissues.
Fig. 2: Elevated expression of PAK4 in aggressive bladder adenocarcinomas.
Fig. 3: Elevated PAK4 activity in a subset of primary BLCAs.
Fig. 4: PAK4 involvement in BLCA cell proliferation and invasion.
Fig. 5: Inhibition of PAK4 by a small molecule inhibitor (PF-3758309) reduces BLCA cell proliferation.
Fig. 6: RNA-seq analysis of VM-CUB1 cells treated with PAK4 siRNA or PF-3758309.

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References

  1. Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71:96–108.

    PubMed  Google Scholar 

  2. von der Maase H, Sengelov L, Roberts JT, Ricci S, Dogliotti L, Oliver T, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23:4602–8.

    PubMed  Google Scholar 

  3. Grossman HB, Natale RB, Tangen CM, Speights VO, Vogelzang NJ, Trump DL, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N. Engl J Med. 2003;349:859–66.

    CAS  PubMed  Google Scholar 

  4. Griffiths G, Hall R, Sylvester R, Raghavan D, Parmar MK. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol. 2011;29:2171–7.

    CAS  PubMed  Google Scholar 

  5. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389:67–76.

    CAS  PubMed  Google Scholar 

  6. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl J Med. 2017;376:1015–26.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Sonpavde G. PD-1 and PD-L1 inhibitors as salvage therapy for urothelial carcinoma. N. Engl J Med. 2017;376:1073–4.

    PubMed  Google Scholar 

  8. Balar AV, Castellano D, O’Donnell PH, Grivas P, Vuky J, Powles T, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18:1483–92.

    CAS  PubMed  Google Scholar 

  9. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25:152–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. McConkey DJ, Choi W, Ochoa A, Siefker-Radtke A, Czerniak B, Dinney CP. Therapeutic opportunities in the intrinsic subtypes of muscle-invasive bladder cancer. Hematol Oncol Clin North Am. 2015;29:377–94. x-xi.

    PubMed  Google Scholar 

  11. Robertson AG, Kim J, Al-Ahmadie H, Bellmunt J, Guo G, Cherniack AD, et al. Comprehensive molecular characterization of muscle-invasive bladder. Cancer Cell 2017;171:540–56. e25.

    CAS  Google Scholar 

  12. Jacobs JJ, van Lohuizen M. Cellular memory of transcriptional states by polycomb-group proteins. Semin Cell Dev Biol. 1999;10:227–35.

    CAS  PubMed  Google Scholar 

  13. Francis NJ, Kingston RE. Mechanisms of transcriptional memory. Nat Rev Mol Cell Biol. 2001;2:409–21.

    CAS  PubMed  Google Scholar 

  14. Sonpavde G, Jones BS, Bellmunt J, Choueiri TK, Sternberg CN. Future directions and targeted therapies in bladder cancer. Hematol Oncol Clin North Am. 2015;29:361–76. x.

    PubMed  Google Scholar 

  15. Bellmunt J, Orsola A, Sonpavde G. Precision and predictive medicine in urothelial cancer: are we making progress? Eur Urol. 2015;68:547–49.

    PubMed  Google Scholar 

  16. Poh A. Erdafitinib efficacious in bladder cancer. Cancer Discov. 2018;8:OF6.

  17. Choudhury NJ, Campanile A, Antic T, Yap KL, Fitzpatrick CA, Wade JL, 3rd. et al. Afatinib activity in platinum-refractory metastatic urothelial carcinoma in patients with ERBB alterations. J Clin Oncol. 2016;34:2165–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science. 2012;338:221.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife. 2015;4:e05005.

  20. Bandiera S, Pfeffer S, Baumert TF, Zeisel MB. miR-122–a key factor and therapeutic target in liver disease. J Hepatol. 2015;62:448–57.

    CAS  PubMed  Google Scholar 

  21. Jian B, Li Z, Xiao D, He G, Bai L, Yang Q. Downregulation of microRNA-193-3p inhibits tumor proliferation migration and chemoresistance in human gastric cancer by regulating PTEN gene. Tumour Biol. 2016;37:8941–9.

    CAS  PubMed  Google Scholar 

  22. Zhang HS, Zhang FJ, Li H, Liu Y, Du GY, Huang YH. Tanshinone A inhibits human esophageal cancer cell growth through miR-122-mediated PKM2 down-regulation. Arch Biochem Biophys. 2016;598:50–6.

    CAS  PubMed  Google Scholar 

  23. Wang Y, Xing QF, Liu XQ, Guo ZJ, Li CY, Sun G. MiR-122 targets VEGFC in bladder cancer to inhibit tumor growth and angiogenesis. Am J Transl Res. 2016;8:3056–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Xu XL, Ye YL, Wu ZM, He QM, Tan L, Xiao KH, et al. Overexpression of PTK6 predicts poor prognosis in bladder cancer patients. J Cancer. 2017;8:3464–73.

    PubMed  PubMed Central  Google Scholar 

  25. Li N, Lopez MA, Linares M, Kumar S, Oliva S, Martinez-Lopez J. et al. Dual PAK4-NAMPT inhibition impacts growth and survival, and increases sensitivity to DNA-damaging agents in Waldenstrom Macroglobulinemia. Clin Cancer Res. 2018;25:369–77.

    PubMed  PubMed Central  Google Scholar 

  26. Phatak P, Burrows WM, Chesnick IE, Tulapurkar ME, Rao JN, Turner DJ, et al. MiR-199a-3p decreases esophageal cancer cell proliferation by targeting p21 activated kinase 4. Oncotarget. 2018;9:28391–407.

    PubMed  PubMed Central  Google Scholar 

  27. Mahlamaki EH, Kauraniemi P, Monni O, Wolf M, Hautaniemi S, Kallioniemi A. High-resolution genomic and expression profiling reveals 105 putative amplification target genes in pancreatic cancer. Neoplasia. 2004;6:432–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Kimmelman AC, Hezel AF, Aguirre AJ, Zheng H, Paik JH, Ying H, et al. Genomic alterations link Rho family of GTPases to the highly invasive phenotype of pancreas cancer. Proc Natl Acad Sci USA. 2008;105:19372–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Tyagi N, Bhardwaj A, Singh AP, McClellan S, Carter JE, Singh S. p-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-kappaB pathway. Oncotarget. 2014;5:8778–89.

    PubMed  PubMed Central  Google Scholar 

  30. Thillai K, Sarker D, Wells C. PAK4 pathway as a potential therapeutic target in pancreatic cancer. Future Oncol. 2018;14:579–82.

    CAS  PubMed  Google Scholar 

  31. Yu W, Kanaan Y, Bae YK, Gabrielson E. Chromosomal changes in aggressive breast cancers with basal-like features. Cancer Genet Cytogenet. 2009;193:29–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Li SQ, Wang ZH, Mi XG, Liu L, Tan Y. MiR-199a/b-3p suppresses migration and invasion of breast cancer cells by downregulating PAK4/MEK/ERK signaling pathway. IUBMB Life. 2015;67:768–77.

    CAS  PubMed  Google Scholar 

  33. Mao K, Lei D, Zhang H, You C. MicroRNA-485 inhibits malignant biological behaviour of glioblastoma cells by directly targeting PAK4. Int J Oncol. 2017;51:1521–32.

    CAS  PubMed  Google Scholar 

  34. Zeng B, Shi W, Tan G. MiR-199a/b-3p inhibits gastric cancer cell proliferation via down-regulating PAK4/MEK/ERK signaling pathway. BMC Cancer. 2018;18:34.

    PubMed  PubMed Central  Google Scholar 

  35. Callegari E, D’Abundo L, Guerriero P, Simioni C, Elamin BK, Russo M, et al. miR-199a-3p Modulates MTOR and PAK4 Pathways and Inhibits Tumor Growth in a Hepatocellular Carcinoma Transgenic Mouse Model. Mol Ther Nucleic Acids. 2018;11:485–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. He LF, Xu HW, Chen M, Xian ZR, Wen XF, Chen MN, et al. Activated-PAK4 predicts worse prognosis in breast cancer and promotes tumorigenesis through activation of PI3K/AKT signaling. Oncotarget. 2017;8:17573–85.

    PubMed  Google Scholar 

  37. Xu HT, Lai WL, Liu HF, Wong LL, Ng IO, Ching YP. PAK4 phosphorylates p53 at serine 215 to promote liver cancer metastasis. Cancer Res. 2016;76:5732–42.

    CAS  PubMed  Google Scholar 

  38. Park JJ, Park MH, Oh EH, Soung NK, Lee SJ, Jung JK. et al. The p21-activated kinase 4-Slug transcription factor axis promotes epithelial-mesenchymal transition and worsens prognosis in prostate cancer. Oncogene. 2018;37:5147–59.

    CAS  PubMed  Google Scholar 

  39. Li Y, Zhang H, Zhao Y, Wang C, Cheng Z, Tang L. et al. A mandatory role of nuclear PAK4-LIFR axis in breast-to-bone metastasis of ERalpha-positive breast cancer cells. Oncogene. 2018;38:808–21.

    PubMed  PubMed Central  Google Scholar 

  40. Petrylak DP, Balar AV, O’Donnell PH, McGregor BA, Heath EI, Yu EY, et al. EV-201: results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. J Clin Oncol. 2019;37:4505-.

    Google Scholar 

  41. Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N. Engl J Med. 2019;381:338–48.

    CAS  PubMed  Google Scholar 

  42. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl J Med. 2015;372:30–9.

    PubMed  Google Scholar 

  43. Rogers MS, Foley MA, Crotty TB, Hartmann LC, Ingle JN, Roche PC, et al. Loss of immunoreactivity for human calmodulin-like protein is an early event in breast cancer development. Neoplasia. 1999;1:220–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Bennett RD, Pittelkow MR, Strehler EE. Immunolocalization of the tumor-sensitive calmodulin-like protein CALML3 in normal human skin and hyperproliferative skin disorders. PLoS ONE. 2013;8:e62347.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Brooks MD, Bennett RD, Weaver AL, Sebo TJ, Eckert SE, Strehler EE, et al. Human calmodulin-like protein CALML3: a novel marker for normal oral squamous mucosa that is downregulated in malignant transformation. Int J Dent. 2013;2013:592843.

    PubMed  PubMed Central  Google Scholar 

  46. Conrad C, Benzel J, Dorzweiler K, Cook L, Schlomann U, Zarbock A, et al. ADAM8 in invasive cancers: links to tumor progression, metastasis, and chemoresistance. Clin Sci. 2019;133:83–99.

    CAS  Google Scholar 

  47. Ravipaty S, Wu W, Dalvi A, Tanna N, Andreazi J, Friss T, et al. Clinical validation of a serum protein panel (FLNA, FLNB and KRT19) for diagnosis of prostate cancer. J Mol Biomark Diagn. 2017;8:323.

  48. Iguchi Y, Ishihara S, Uchida Y, Tajima K, Mizutani T, Kawabata K, et al. Filamin B enhances the invasiveness of cancer cells into 3D Collagen Matrices. Cell Struct Funct. 2015;40:61–7.

    CAS  PubMed  Google Scholar 

  49. Chen C, Shan H. Keratin 6A gene silencing suppresses cell invasion and metastasis of nasopharyngeal carcinoma via the betacatenin cascade. Mol Med Rep. 2019;19:3477–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Ricciardelli C, Lokman NA, Pyragius CE, Ween MP, Macpherson AM, Ruszkiewicz A, et al. Keratin 5 overexpression is associated with serous ovarian cancer recurrence and chemotherapy resistance. Oncotarget. 2017;8:17819–32.

    PubMed  PubMed Central  Google Scholar 

  51. Xiao J, Lu X, Chen X, Zou Y, Liu A, Li W, et al. Eight potential biomarkers for distinguishing between lung adenocarcinoma and squamous cell carcinoma. Oncotarget. 2017;8:71759–71.

    PubMed  PubMed Central  Google Scholar 

  52. Puvirajesinghe TM, Bertucci F, Jain A, Scerbo P, Belotti E, Audebert S, et al. Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2-JNK signalling in breast cancer. Nat Commun. 2016;7:10318.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, et al. Activating smoothened mutations in sporadic basal-cell carcinoma. Nature. 1998;391:90–2.

    CAS  PubMed  Google Scholar 

  54. Huang XH, Chen JS, Wang Q, Chen XL, Wen L, Chen LZ, et al. miR-338-3p suppresses invasion of liver cancer cell by targeting smoothened. J Pathol. 2011;225:463–72.

    CAS  PubMed  Google Scholar 

  55. Ye L, Li F, Song Y, Yu D, Xiong Z, Li Y, et al. Overexpression of CDCA7 predicts poor prognosis and induces EZH2-mediated progression of triple-negative breast cancer. Int J Cancer. 2018;143:2602–13.

    CAS  PubMed  Google Scholar 

  56. Wang H, Ye L, Xing Z, Li H, Lv T, Liu H, et al. CDCA7 promotes lung adenocarcinoma proliferation via regulating the cell cycle. Pathol Res Pr. 2019;215:152559.

    CAS  Google Scholar 

  57. Grizzle WEBW, Fredenburgh J. Safety in biomedical and other laboratories. In: Patrinos G, Ansorg W, Editors. Molecular Diagnostics. USA: Elsevier Academic Press; Chapter 33, pp 421–8, 2005.

  58. Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25:1754–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A, et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20:1297–303.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43:491–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Cibulskis K, Lawrence MS, Carter SL, Sivachenko A, Jaffe D, Sougnez C, et al. Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples. Nat Biotechnol. 2013;31:213–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Koboldt DC, Zhang Q, Larson DE, Shen D, McLellan MD, Lin L, et al. VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. Genome Res. 2012;22:568–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.

    PubMed  PubMed Central  Google Scholar 

  64. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, et al. The sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25:2078–9.

    PubMed  PubMed Central  Google Scholar 

  65. Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, Horsman D, et al. Circos: an information aesthetic for comparative genomics. Genome Res. 2009;19:1639–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL, et al. Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol. 2008;26:317–25.

    CAS  PubMed  Google Scholar 

  67. Anderson JC, Willey CD, Mehta A, Welaya K, Chen D, Duarte CW, et al. High throughput kinomic profiling of human clear cell renal cell carcinoma identifies kinase activity dependent molecular subtypes. PLoS ONE. 2015;10:e0139267.

    PubMed  PubMed Central  Google Scholar 

  68. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    PubMed  PubMed Central  Google Scholar 

  69. Chandrashekar DS, Bashel B, Balasubramanya SAH, Creighton CJ, Ponce-Rodriguez I, Chakravarthi B, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017;19:649–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kim D, Pertea G, Trapnell C, Pimentel H, Kelley R, Salzberg SL. TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions. Genome Biol. 2013;14:R36.

    PubMed  PubMed Central  Google Scholar 

  71. Li H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics. 2011;27:2987–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Anders S, Pyl PT, Huber W. HTSeq–a Python framework to work with high-throughput sequencing data. Bioinformatics. 2015;31:166–9.

    CAS  PubMed  Google Scholar 

  73. Anders S, Huber W. Differential expression analysis for sequence count data. Genome Biol. 2010;11:R106.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Chakravarthi B, Rodriguez Pena MDC, Agarwal S, Chandrashekar DS, Hodigere Balasubramanya SA, Jabboure FJ, et al. A role for de novo purine metabolic enzyme PAICS in bladder cancer progression. Neoplasia. 2018;20:894–904.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45:D362–8.

    CAS  PubMed  Google Scholar 

  76. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28:27–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene Suite for gene list enrichment analysis and candidate gene prioritization. Nucleic Acids Res. 2009;37:W305–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Han H, Cho JW, Lee S, Yun A, Kim H, Bae D, et al. TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions. Nucleic Acids Res. 2018;46:D380–6.

    CAS  PubMed  Google Scholar 

  80. Hao JQ, Li Q, Xu SP, Shen YX, Sun GY. Effect of lumiracoxib on proliferation and apoptosis of human nonsmall cell lung cancer cells in vitro. Chin Med J. 2008;121:602–7.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported in part by institutional funds (Department of Pathology and School of Medicine of the University of Alabama at Birmingham) awarded to SV. IBAB is supported by the Department of IT, BT and S&T, Government of Karnataka, India. The authors thank Dr Donald Hill for critical reading and editing of this manuscript.

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Author notes

  1. These authors contributed equally: Darshan S. Chandrashekar, Balabhadrapatruni V. S. K. Chakravarthi

  2. These authors jointly supervised this work: Sooryanarayana Varambally, Guru Sonpavde

Authors and Affiliations

  1. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    Darshan S. Chandrashekar, Balabhadrapatruni V. S. K. Chakravarthi, Alyncia D. Robinson, Sumit Agarwal, Sai Akshaya Hodigere Balasubramanya, Marie-Lisa Eich, Upender Manne, William E. Grizzle, George J. Netto & Sooryanarayana Varambally

  2. Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    Joshua C. Anderson, Deborah L. Della Manna, Christopher D. Willey & Eddy S. Yang

  3. Shodhaka Life Sciences Private Limited, Bengaluru, India

    Akhilesh Kumar Bajpai, Sravanthi Davuluri & Kshitish K. Acharya

  4. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Maya S. Guru & Arjun S. Guru

  5. Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    Gurudatta Naik

  6. O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    Gurudatta Naik, Upender Manne, George J. Netto, Eddy S. Yang & Sooryanarayana Varambally

  7. Institute of Bioinformatics and Applied Biotechnology (IBAB), Biotech Park, Electronic City, Bengaluru, 560100, Karnataka, India

    Kshitish K. Acharya

  8. Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, 48202, USA

    Shannon Carskadon & Nallasivam Palanisamy

  9. Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA

    David K. Crossman & Michael R. Crowley

  10. Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA

    James E. Ferguson, William E. Grizzle & Christopher D. Willey

  11. Informatics Institute, University of Alabama at Birmingham, Birmingham, AL, USA

    Sooryanarayana Varambally

  12. Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA

    Guru Sonpavde

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  1. Darshan S. Chandrashekar
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Correspondence to Sooryanarayana Varambally or Guru Sonpavde.

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GS was a consultant for BMS, Exelixis, Bayer, Sanofi, Pfizer, Novartis, Eisai, Janssen, Amgen, AstraZeneca, Merck, Genentech, Astellas/Agensys; Research support to institution from Bayer, Amgen, Boehringer-Ingelheim, Merck, Sanofi, Pfizer; Author for Up-to-date; Speaker for Clinical Care Options, Physicians Education Resource (PER), Research to Practice (RTP), Onclive. CW was a consultant for Varian Medical Systems and LifeNet Health, Inc. AB and SD received financial support from Shodhaka LS Pvt. Ltd. KKA is the founder and director of Shodhaka LS Pvt. Ltd. GJN served as a consultant to Genentec. ESY was a consultant for Astrazeneca; Research support to institution from Astrazeneca, Eli Lilly, Novartis.

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Chandrashekar, D.S., Chakravarthi, B.V.K., Robinson, A.D. et al. Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression. Oncogene 39, 4077–4091 (2020). https://doi.org/10.1038/s41388-020-1275-7

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