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

Autor: Chandrashekar DS; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Chakravarthi BVSK; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Robinson AD; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Anderson JC; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Agarwal S; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Balasubramanya SAH; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Eich ML; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Bajpai AK; Shodhaka Life Sciences Private Limited, Bengaluru, India., Davuluri S; Shodhaka Life Sciences Private Limited, Bengaluru, India., Guru MS; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Guru AS; Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA., Naik G; Division of Hematology and Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA., Della Manna DL; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA., Acharya KK; Shodhaka Life Sciences Private Limited, Bengaluru, India.; Institute of Bioinformatics and Applied Biotechnology (IBAB), Biotech Park, Electronic City, Bengaluru, 560100, Karnataka, India., Carskadon S; Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, 48202, USA., Manne U; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA., Crossman DK; Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA., Ferguson JE; Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA., Grizzle WE; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.; Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA., Palanisamy N; Vattikuti Urology Institute, Department of Urology, Henry Ford Health System, Detroit, MI, 48202, USA., Willey CD; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.; Department of Urology, University of Alabama at Birmingham, Birmingham, AL, USA., Crowley MR; Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA., Netto GJ; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA., Yang ES; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA., Varambally S; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA. svarambally@uabmc.edu.; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. svarambally@uabmc.edu.; Informatics Institute, University of Alabama at Birmingham, Birmingham, AL, USA. svarambally@uabmc.edu., Sonpavde G; Department of Medicine, Dana-Farber Cancer Institute, Boston, MA, USA. GuruP_Sonpavde@DFCI.HARVARD.EDU.
Jazyk: angličtina
Zdroj: Oncogene [Oncogene] 2020 May; Vol. 39 (20), pp. 4077-4091. Date of Electronic Publication: 2020 Mar 30.
DOI: 10.1038/s41388-020-1275-7
Abstrakt: 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.
Databáze: MEDLINE
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