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

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.

Oncogene. 2020 Mar 30 [Epub ahead of print]

Darshan S Chandrashekar, Balabhadrapatruni V S K Chakravarthi, Alyncia D Robinson, Joshua C Anderson, Sumit Agarwal, Sai Akshaya Hodigere Balasubramanya, Marie-Lisa Eich, Akhilesh Kumar Bajpai, Sravanthi Davuluri, Maya S Guru, Arjun S Guru, Gurudatta Naik, Deborah L Della Manna, Kshitish K Acharya, Shannon Carskadon, Upender Manne, David K Crossman, James E Ferguson, William E Grizzle, Nallasivam Palanisamy, Christopher D Willey, Michael R Crowley, George J Netto, Eddy S Yang, Sooryanarayana Varambally, Guru Sonpavde

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Shodhaka Life Sciences Private Limited, Bengaluru, India., Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, 48202, USA., Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA., Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA., Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. ., Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA. .

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