Analysis of mTOR Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K-AKT-mTOR Pathway Inhibitors

Purpose: mTOR is a validated target in cancer. It remains to be determined whether melanoma patients bearing mTOR mutation could be selected for treatment with PI3K-AKT-mTOR pathway inhibitors. Experimental Design: A total of 412 melanoma samples were included. Gene aberrations in all exons of mTOR were detected by Sanger sequencing and confirmed by using Agilent's SureSelect Target Enrichment System. HEK293T cells stably expressing mTOR mutants were constructed by using transcription activator- like effector nucleases technique. Function of mTOR mutants and in vitro sensitivity of gain-of-function mTOR mutations to PI3K-AKT-mTOR pathway inhibitors were analyzed. Results: The overall incidence of somatic nonsynonymous mutations of mTOR was 10.4% (43/412). mTOR nonsynonymous mutations were relatively more frequent in acral (11.0%) and mucosal (14.3%) melanomas than in chronic sun-induced damage (CSD; 6.7%) and non-CSD (3.4%) mela-nomas. Of the 43 cases with mTOR mutations, 41 different mutations were detected, affecting 25 different exons. The median survival time for melanoma patients with mTOR nonsynonymous mutation was significantly shorter than that for patients without mTOR nonsynonymous mutation (P = 0.028). Transient expression of mTOR mutants in HEK293T cells strongly activated the mTOR-p70S6K pathway. In HEK293T cells with stable expression of H1968Y or P2213S mTOR mutants, LY294002 and AZD5363 showed higher potency than temsirolimus or BYL719 in inhibiting the PI3K-AKT-mTOR pathway and cell proliferation. Conclusions: mTOR nonsynonymous mutations are frequent in melanoma patients. mTOR nonsynonymous mutation may predict a worse prognosis of melanoma. Clinical trials with PI3K-AKT-mTOR pathway inhibitors may be beneficial for melanoma patients with specific mTOR mutations. (C) 2015 AACR.