Oncogene. 2020 Mar 30. doi: 10.1038/s41388-020-1275-7. [Epub ahead of print]
Therapeutically actionable PAK4 is amplified, overexpressed, and involved in bladder cancer progression.
Chandrashekar DS1, Chakravarthi BVSK1, Robinson AD1, Anderson JC2, Agarwal S1, Balasubramanya SAH1, Eich ML1, Bajpai AK3, Davuluri S3, Guru MS4, Guru AS4, Naik G5,6, Della Manna DL2, Acharya KK3,7, Carskadon S8, Manne U1,6, Crossman DK9, Ferguson JE10, Grizzle WE1,10, Palanisamy N8, Willey CD2,10, Crowley MR9, Netto GJ1,6, Yang ES2,6, Varambally S11,12,13, Sonpavde G14.
Author information
- 1
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.
- 2
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
- 3
- Shodhaka Life Sciences Private Limited, Bengaluru, India.
- 4
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
- 5
- Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
- 6
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA.
- 7
- Institute of Bioinformatics and Applied Biotechnology (IBAB), Biotech Park, Electronic City, Bengaluru, 560100, Karnataka, India.
- 8
- Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, 48202, USA.
- 9
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
- 10
- Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA.
- 11
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. svarambally@uabmc.edu.
- 12
- O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. svarambally@uabmc.edu.
- 13
- Informatics Institute, University of Alabama at Birmingham, Birmingham, AL, USA. svarambally@uabmc.edu.
- 14
- Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA. GuruP_Sonpavde@DFCI.HARVARD.EDU.
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.
- PMID:
- 32231273
- DOI:
- 10.1038/s41388-020-1275-7
