TY - JOUR T1 - Therapeutically actionable PAK4 is amplified, overexpressed and involved in bladder cancer progression JF - bioRxiv DO - 10.1101/740316 SP - 740316 AU - Darshan S. Chandrashekar AU - Balabhadrapatruni V. S. K. Chakravarthi AU - Alyncia D. Robinson AU - Joshua C. Anderson AU - Sumit Agarwal AU - Sai Akshaya Hodigere Balasubramanya AU - Marie-Lisa Eich AU - Akhilesh Kumar Bajpai AU - Sravanthi Davuluri AU - Maya S. Guru AU - Arjun S. Guru AU - Gurudatta Naik AU - Deborah L. Della Manna AU - Kshitish K. Acharya AU - Shannon Carskadon AU - Upender Manne AU - David K. Crossman AU - James E. Ferguson AU - William E. Grizzle AU - Nallasivam Palanisamy AU - Christopher D. Willey AU - Michael R. Crowley AU - George J Netto AU - Eddy S. Yang AU - Sooryanarayana Varambally AU - Guru Sonpavde Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/08/20/740316.abstract N2 - Muscle-invasive bladder carcinomas (MIBCs) are aggressive genitourinary malignancies. Disease incidence and survival rates vary based on aggressiveness and treatment options. Metastatic urothelial carcinoma of the bladder is generally incurable by current chemotherapy and leads to early mortality. For a minority (∼20%) of patients, T-cell checkpoint inhibitors provide durable benefits following prior platinum therapy. Recent studies have identified molecular subtypes of MIBCs with different sensitivities to frontline therapy, suggesting heterogeneity in these tumors and pointing to the importance of molecular characterization of MIBCs to provide effective treatment. We have performed multi-omic profiling of the kinome to identify therapeutic targets that are overexpressed in a subset of BLCAs. Our analyses revealed amplification and overexpression of P21 (RAC1) activated kinase 4 (PAK4) in a subset of BLCAs. For these tumors, multiplex kinase assay profiling identified corresponding PAK4 target substrates. By performing experiments using cultured bladder cancer cells, we confirmed the role of PAK4 in BLCA cell proliferation and invasion. Furthermore, our studies showed 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. Similarly, RNA interference of PAK4 led to elevated expression of PTK6. Treatment with a combination of kinase inhibitors (vandetanib and dasatinib) showed enhanced sensitivity compared to 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. ER -