PAK4 as a Promising New Therapeutic Target in Aggressive Bladder Cancer - Beyond the Abstract

Urothelial carcinoma (UC) of the bladder is a tremendously heterogeneous malignancy characterized by multiple kinase drivers. Activating mutations of the FGFR3, PIK3CA, ERBB2, and mTOR kinase genes have all been observed in subsets of patients with UC. FGFR inhibitors have demonstrated 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 activating mutations/fusions based on responses in ~40% of these patients.

However, metastatic UC remains an incurable malignancy for the most part despite recent additions of PD1/L1 inhibitors and enfortumab vedotin (antibody-drug conjugate) to the therapeutic arsenal. We hypothesized that other unrecognized kinases may be relevant drivers of this malignancy even without genomic alterations. Furthermore, the relative ease of designing kinase inhibitors provided the impetus to conduct this project. We evaluated tumors derived from patients with muscle-invasive bladder cancer (MIBC) to interrogate ~500 kinases on multiple molecular platforms including kinomics (protein kinase activity profiling using PamStation® microarray), transcriptomics (NanoString®) and genomics (next-generation sequencing) profiling. The impact of the altered kinase was further studied in the Cancer Genome Atlas (TCGA) and preclinical systems.

Our study identified the PAK4 kinase to be amplified and overexpressed in up to 12% of MIBC. Additionally, PAK4 functional activity appeared to occur in ~33% of the analyzed MIBCs, which may be explained by frequent post-transcriptional regulation of kinases. PAK4 is a member of 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 database. Furthermore, preclinical PAK4 inhibition led to the upregulation of PTK6, and co-targeting both of these kinases exhibited more robust anti-tumor activity. Thus, PAK4 may be therapeutically actionable in a subset of MIBC and metastatic UC patients. Validation of PAK4 as a therapeutic target in a preclinical animal model bearing human tumors harboring PAK4 amplification, overexpression or functional activation of PAK4 is warranted to provide the rationale for a clinical trial in rationally selected patients with MIBC and metastatic UC.

Written by: Guru Sonpavde, MD, Director of the Bladder Cancer Program, Dana Farber Cancer Institute, Boston, Massachusetts, Twitter: @sonpavde, and Sooryanarayana Varambally, PhD, Director of Translational Oncologic Pathology Research at UAB pathology, University of Alabama at Birmingham (UAB), Birmingham, Alabama, Twitter: @Varambally_S

Read the Abstract