Analysis of the PI3K-AKT-mTOR pathway in penile cancer: evaluation of a therapeutically targetable pathway

To determine whether phosphatidylinositol-4,5-bisphosphate 3- kinase, catalytic subunit alpha (PIK3CA) copy number gain is common and could prove a useful marker for the activation status of the PI3K-AKT-mTOR pathway in penile squamous cell carcinoma (PSCC).

Fresh frozen tissue and archival blocks were collected from 24 PSCC patients with 15 matched normal penile epithelium (NPE) tissue from St George's Hospital. PIK3CA mutational and copy number status (CNS) was assessed via Sanger sequencing and fluorescence in-situ hybridisation, respectively. PIK3CA RNA expression was quantified using TaqMan gene expression assay. HPV DNA was detected with INNO-LiPA assay. p-AKT and p-mTOR protein expression were assessed using western blot and immunohistochemistry.

PIK3CA copy number gain was found in 11/23 (48%) patients, with mutations present in only 2/24 (8%) patients. In comparison to NPE, PSCC showed significantly lower PIK3CA RNA expression (p=0.0007), p-AKT (Ser473) nuclear immunoexpression (p=0.026) and protein expression of p-AKT (Thr308) (p=0.0247) and p-mTOR (Ser2448) (p=0.0041). No association was found between PIK3CA CNS and p-AKT and p-mTOR protein expression.

Based on our results the PI3K-AKT-mTOR pathway is not a key driver in PSCC carcinogenesis and the therapeutic targeting of this pathway is unlikely to produce significant clinical benefit.

Oncotarget. 2018 Mar 23*** epublish ***

Anthony Adimonye, Elzbieta Stankiewicz, Sakunthala Kudahetti, Giorgia Trevisan, Brendan Tinwell, Cathy Corbishley, Yong-Jie Lu, Nick Watkin, Daniel Berney

Centre for Molecular Oncology, Bart's Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom., Department of Histopathology, Royal London Hospital, Barts Health NHS Trust, London, United Kingdom., Department of Cellular Pathology, St George's Hospital, London, United Kingdom., Department of Urology, St George's Hospital, London, United Kingdom.