Oncotarget

Research Papers:

BRAFV600E-dependent Mcl-1 stabilization leads to everolimus resistance in colon cancer cells

Kan He, Dongshi Chen, Hang Ruan, Xiangyun Li, Jingshan Tong, Xiang Xu, Lin Zhang and Jian Yu _

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Oncotarget. 2016; 7:47699-47710. https://doi.org/10.18632/oncotarget.10277

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Abstract

Kan He1,2, Dongshi Chen2,3, Hang Ruan1,2, Xiangyun Li1,2,4, Jingshan Tong2,3, Xiang Xu4, Lin Zhang2,3, Jian Yu1,2

1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

2University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

3Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA

4The Third Military Medical University Daping Hospital, Daping, Yu Zhong District, Chongqing 400042, P.R. China

Correspondence to:

Jian Yu, email: [email protected]

Keywords: mTOR, everolimus, Mcl-1, BRAF V600E, ERK

Received: March 22, 2016     Accepted: June 09, 2016     Published: June 24, 2016

ABSTRACT

mTOR activation is commonly caused by oncogenic mutations in RAS/RAF/MAPK and PI3K/AKT pathways, and promotes cancer progression and therapeutic resistance. However, mTOR inhibitors show limited single agent efficacy in patients. mTOR inhibitors suppress tumor cell growth and angiogenesis, and have recently been shown to induce death receptor/FADD-dependent apoptosis in colon cancers. Using a panel of BRAF V600E and WT colorectal cancer cell lines and in vitro selected resistant culture, and xenograft models, we demonstrate here that BRAFV600E confers resistance to mTOR inhibitors. Everolimus treatment disrupts the S6K1-IRS-2/PI3K negative feedback loop, leading to BRAF V600E-dependent activation of ERK and Mcl-1 stabilization in colon cancer cells, which in turn blocks the crosstalk from the death receptor to mitochondria. Co-treatment with inhibitors to Mcl-1, PI3K, RAF or MEK restores mTOR inhibitor-induced apoptosis by antagonizing Mcl-1 or abrogating ERK activation in BRAFV600E cells. Our findings provide a rationale for genotype-guided patient stratification and potential drug combinations to prevent or mitigate undesired activation of survival pathways induced by mTOR inhibitors.


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