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

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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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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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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