Whereas the lack of biomarkers in penile cancer (PeCa) impedes the development of efficacious treatment protocols, preliminary evidence suggests that c-MET and associated signaling elements may be dysregulated in this disorder. In the following study, we investigated whether c-MET and associated key molecular elements may have prognostic and therapeutic utility in PeCa. Formalin-fixed, paraffin-embedded tumor tissue from therapy-naïve patients with invasive PeCa was used for tissue microarray (TMA) analysis. Immunohistochemical staining was performed to determine the expression of the proteins c-MET, PPARg, β-catenin, snail, survivin, and n-MYC. In total, 94 PeCa patients with available tumor tissue were included. The median age was 64.9 years. High-grade tumors were present in 23.4%, and high-risk HPV was detected in 25.5%. The median follow-up was 32.5 months. High expression of snail was associated with HPV-positive tumors. Expression of β-catenin was inversely associated with grading. In both univariate COX regression analysis and the log-rank test, an increased expression of PPARg and c-MET was predictive of inferior disease-specific survival (DSS). Moreover, in multivariate analysis, a higher expression of c-MET was independently associated with worse DSS. Blocking c-MET with cabozantinib and tivantinib induced a significant decrease in viability in the primary PeCa cell line UKF-PeC3 isolated from the tumor tissue as well as in cisplatin- and osimertinib-resistant sublines. Strikingly, a higher sensitivity to tivantinib could be detected in the latter, pointing to the promising option of utilizing this agent in the second-line treatment setting.
Cancers. 2022 Mar 25*** epublish ***
Anita Thomas, Kimberly Sue Slade, Roman A Blaheta, Sascha D Markowitsch, Philipp Stenzel, Katrin E Tagscherer, Wilfried Roth, Mario Schindeldecker, Martin Michaelis, Florian Rothweiler, Jaroslav Cinatl, Robert Dotzauer, Olesya Vakhrusheva, Maarten Albersen, Axel Haferkamp, Eva Juengel, Jindrich Cinatl, Igor Tsaur
Department of Urology and Pediatric Urology, University Medicine Mainz, 55131 Mainz, Germany., Department of Pathology, University Medicine Mainz, 55131 Mainz, Germany., Industrial Biotechnology Centre, School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK., Institute of Medical Virology, Goethe-University, 60596 Frankfurt am Main, Germany., Department of Urology, University Hospitals Leuven, 28046 Leuven, Belgium.