Urothelial carcinoma (UC) of the bladder is a highly heterogeneous malignancy characterized by multiple kinase drivers. Indeed, activating mutations of the FGFR3, PIK3CA, ERBB2, and mTOR kinase genes have all been observed in subsets of UC. FGFR inhibitors have activity for the subset of 15-20% of patients with FGFR3-altered metastatic UC. Erdafitinib was recently approved for post-platinum patients with genomic FGFR3/2 alterations based on responses in ~40% of these patients.
Metastatic UC is a generally incurable malignancy despite recent additions of immune checkpoint inhibitors and Enfortumab Vedotin (antibody drug conjugate) to the therapeutic arsenal. Other kinase driven pathways may be relevant drivers of this malignancy even without genomic mutations. This hypothesis in conjunction with the relative ease of designing kinase inhibitors provided the impetus to undertake this project. We evaluated tumors derived from patients with muscle-invasive bladder cancer (MIBC) to interrogate ~500 kinases on multiple molecular platforms including kinomic (protein kinase activity profiling using Pamstation microarray), transcriptomic (Nanostring) and genomic (Next Generation Sequencing) profiling. The altered kinase was further characterized and functionally validated in the Cancer Genome Atlas (TCGA) and in preclinical systems.
Our study identified the PAK4 kinase as amplified and overexpressed in up to 12% of MIBC. Moreover, PAK4 functional activity is observed in ~33% of the analyzed MIBCs, which may be explained by frequent post-transcriptional regulation. PAK4 belongs to a family of serine/threonine kinases involved in cell proliferation and migration and cytoskeletal organization. PAK4 amplification was associated with worse survival in MIBC patients undergoing radical cystectomy in the TCGA dataset. Furthermore, preclinical PAK4 inhibition led to upregulation of PTK6, and co-targeting both of these kinases conferred more robust anti-tumor activity. Thus, PAK4 may be therapeutically actionable for a subset of MIBC patients. Validation of PAK4 as a therapeutic target in a preclinical model bearing human tumors harboring PAK4 amplification, overexpression or functional activation of PAK4 may be warranted to provide the rationale for a clinical trial in rationally selected patients with MIBC and metastatic UC.
Written by Guru Sonpavde, MD, Dana-Farber Cancer Institute, Harvard Medical School. Additional contributors, Sooryanarayana Varambally, Ph.D. and Darshan S. Chandrashekar, Ph.D. Department of Pathology, University of Alabama at Birmingham.
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