Value of c-MET and Associated Signaling Elements for Predicting Outcomes and Targeted Therapy in Penile Cancer

SIMPLE SUMMARY: No relevant improvement in patient outcomes could be achieved in the last decade in metastasized penile cancer due to insufficient identification of molecular hubs crucial for tumor evolution. We investigated the potential of the cellular receptor c-MET and selected other proteins linked to its activity to predict outcomes and for exploitation in targeted treatment. Assessing tumor tissue as well as primary cells both naïve and resistant to systemic drugs, we illustrate the most promising role of c-MET. Indeed, its elevated expression was strongly associated with inferior tumor-related survival. Moreover, its upregulation in treatment-resistant cell lines compared to naïve cells was observed. Treating cell lines with the c-MET inhibitors cabozantinib and tivantinib mediated an effective decrease in cell growth, while the first agent was more efficacious in the naïve cells and the second agent in the resistant cells. Therefore, c-MET blockade warrants further investigation in the setting of metastasized penile cancer. ABSTRACT: 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.