Assessment of PI3K/mTOR/AKT Pathway Elements to Serve as Biomarkers and Therapeutic Targets in Penile Cancer.

The PI3K/mTOR/AKT pathway might represent an intriguing option for treatment of penile cancer (PeCa). We aimed to assess whether members of this pathway might serve as biomarkers and targets for systemic therapy. Tissue of primary cancer from treatment-naïve PeCa patients was used for tissue microarray analysis. Immunohistochemical staining was performed with antibodies against AKT, pAKT, mTOR, pmTOR, pS6, pPRAS, p4EBP1, S6K1 and pp70S6K. Protein expression was correlated with clinicopathological characteristics as well as overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and metastasis-free survival (MFS). AKT inhibition was tested in two primarily established, treatment-naïve PeCa cell lines by treatment with capivasertib and analysis of cell viability and chemotaxis. A total of 76 patients surgically treated for invasive PeCa were included. Higher expression of AKT was significantly more prevalent in high-grade tumors and predictive of DSS and OS in the Kaplan-Meier analysis, and an independent predictor of worse OS and DSS in the multivariate regression analysis. Treatment with pan-AKT inhibitor capivasertib in PeCa cell lines induced a significant downregulation of both total AKT and pAKT as well as decreased cell viability and chemotaxis. Selected protein candidates of the mTOR/AKT signaling pathway demonstrate association with histological and survival parameters of PeCa patients, whereas AKT appears to be the most promising one.

Cancers. 2021 May 12*** epublish ***

Anita Thomas, Sascha Reetz, Philipp Stenzel, Katrin Tagscherer, Wilfried Roth, Mario Schindeldecker, Martin Michaelis, Florian Rothweiler, Jindrich Cinatl, Jaroslav Cinatl, Robert Dotzauer, Olesya Vakhrusheva, Maarten Albersen, Stephan Macher-Goeppinger, Axel Haferkamp, Eva Juengel, Andreas Neisius, Igor Tsaur

Department of Urology and Pediatric Urology, University Medicine Mainz, 55122 Mainz, Germany., Department of Pathology, University Medicine Mainz, 55122 Mainz, Germany., Industrial Biotechnology Centre and 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, 3000 Leuven, Belgium.