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

Medientyp: E-Artikel

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

Beteiligte: Thomas, Anita; Slade, Kimberly Sue; Blaheta, Roman A.; Markowitsch, Sascha D.; Stenzel, Philipp; Tagscherer, Katrin E.; Roth, Wilfried; Schindeldecker, Mario; Michaelis, Martin; Rothweiler, Florian; Cinatl, Jaroslav; Dotzauer, Robert; Vakhrusheva, Olesya; Albersen, Maarten; Haferkamp, Axel; Juengel, Eva; Cinatl, Jindrich; Tsaur, Igor

Erschienen: MDPI AG, 2022

Sprache: Englisch

DOI: 10.3390/cancers14071683

ISSN: 2072-6694

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Beschreibung: 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.

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