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

Abstract

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%) melanomas. 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. Clin Cancer Res; 22(4); 1018–27. ©2015 AACR.

Pristimerin attenuates cell proliferation of uveal melanoma cells by inhibiting insulin‐like growth factor‐1 receptor and its downstream pathways

“…Clinical trials with the inhibitors of PI3K/AKT/mTOR pathways may be favourable for melanoma patients with specific mTOR mutations. 31 In the present work, it was found that IGF-1 improved the UM cell Hence, this result was consistent with the finding that treatment of melanoma with selected signalling kinase inhibitors can effectively decrease proliferation and increase expression of cell cycle inhibitors. 33 According to the aforementioned molecular docking suggestions, PRI was a potent inhibitor of IGF-1R, which is consistent with previous reports that compounds with good binding affinity to the IGF-1R tyrosine kinase have potent activity in the inhibition of cell growth.…”

Cryptolepine inhibits melanoma cell growth through coordinated changes in mitochondrial biogenesis, dynamics and metabolic tumor suppressor AMPKα1/2-LKB1

“…The mechanistic target of rapamycin (mTOR) plays a crucial role in multiple cellular processes including protein synthesis, cell growth, cell cycle, cell survival, and autophagy 32 . mTOR has been shown to be activated in the majority of malignant melanomas 33, 34 . Cross-talk between AMPK and mTOR signaling is crucial for regulating cellular metabolism, energy homeostasis, cell growth and cell survival and a growing body of evidence indicates that AMPK activation negatively regulates the mTOR signaling pathway 35, 36 .…”

Expression and clinical significance of C14orf166 in esophageal squamous cell carcinoma

“…Dysfunction of GSK-3β is prevalent in tumor formation, promoting progression and contributing to drug resistance by interfering with signaling pathways, including phosphatidylinositol-3-kinase (PI3K)-protein kinase B (AKT)-mammalian target of rapamycin (mTOR), Wnt/β-catenin and JAK2/STAT3 signaling pathways (26–28). Abnormal expression of PI3K-AKT-mTOR is frequent in melanoma and indicates a poor prognosis, and thus inhibition of the mTOR pathway will benefit numerous patients in the clinic (29). Ge et al (30) demonstrated that through abnormal activation of Wnt/β-catenin pathway, miR-942 aided to maintain cancer stem cell-like traits in ESCC, inducing poor prognosis and unsatisfactory drug effects.…”