Preclinical Evidence for Targeting PI3K/mTOR Signaling with Dual-Inhibitors as a New Therapeutic Strategy against Cutaneous T Cell Lymphoma.

Abstract

The PI3K/AKT/mTOR pathway is hyperactivated in many tumors, as well as in cutaneous T-cell lymphoma (CTCL) which includes mycosis fungoides (MF) and the aggressive variant known as Sezary syndrome (SS). TORC1 signaling is activated in SS cells by cytokines and chemokines, which are overexpressed in SS tissues. Furthermore, the recurrent copy number variation (CNV) of genes belonging to this cascade, such as PTEN, LKB1, and P70S6K, contributes to the hyperactivation of the pathway. The aim of this study was to investigate the therapeutic potential of mTOR inhibitors in CTCL. We compared the efficacy of three rapalogs (rapamycin, temsirolimus and everolimus) and the dual-mTOR/PI3K inhibitor PF-04691502 (hereinafter PF-502) in four CTCL cell lines. PF-502 showed to be the most effective inhibitor of cell growth. Interestingly, PF-502 confirmed its antitumor activity also in patient-derived CTCL cells and in a xenograft mouse model, where it induced significant apoptosis and increased survival of treated mice. Furthermore, we found an inverse correlation between PTEN gene expression and the ability of PF-502 to induce apoptosis in SS cells. Our data strongly support the therapeutic potential of dual PI3K/mTOR inhibitors in CTCL.