Analysis of mTOR Gene Aberrations in Melanoma Patients and Evaluation of Their Sensitivity to PI3K-AKT-mTOR Pathway Inhibitors
PUBLISHED: 2015-12-29  1332 total views, 4 today

Yan Kong1Lu Si1yiqian Li1Xiaowei Wu1Xaiowei Xu2Jie Dai1Huan Tang1,Meng Ma1Zhihong Chi3Xinan Sheng1Chuanliang Cui1, and Jun Guo1,*

Author Affiliations

1Department of Renal cancer and Melanoma, Peking University Cancer Hospital & Institute

2Pathology and Laboratory Medicine, University of Pennsylvania

3Department of Renal Cancer and Melanoma, Peking University Cancer Hospital & Institute

*Corresponding Author:
Jun Guo, Department of Renal cancer and Melanoma, Peking University Cancer Hospital & Institute, 52 Fucheng Road, Beijing, 100142, China guoj307@126.com

Abstract

Purpose: Mammalian target of rapamycin (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: 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 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.

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


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Author
Dr. Guo Jun
+ Author Profile

Dr. Guo Jun

Chief physician, professor, doctoral supervisor, CSCO membership.

The current vice president of Beijing cancer hospital, deputy director of theBeijing Institute for Cancer Research, head of department of renal cancer andmelanoma, Chinese Society Of Clinical Oncology (CSCO) executive board member,CSCO melanoma and renal cancer expert committee director member, Member of Global Melanoma Task Force(GMTF), 


Melanoma international Foudation(MIF) overseas consultant, penner of «NCCN Guidelines for Kidney Cancer (Chinese version)»,«Chinese Melanoma Diagnosis and Treatment Consensus» and «Chinese Guidelinesfor Melanoma Diagnosis and Treatment», entrant of "New Century Excellent Talents Support Plan" hold by Ministry of Education, special review expertof « Melanoma Research », « Journal of Cancer Research and Clinical Oncology »and « Chinese Journal Of Clinical Oncology», evaluation expert of NationalNatural Science Foundation, 


Has published more than 10 articles on famous medical journals, as project director, has undertaken several National Natural Science Foundations.

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