BRAFV600E-dependent Mcl-1 stabilization leads to everolimus resistance in colon cancer cells / 中国药理学与毒理学杂志

ABSTRACT

mTOR is commonly activated in human cancer and an attractive therapeutic target.Its activation is caused primarily by oncogenic mutations in RAS/RAF/MAPK and PI3K/AKT pathways, which cooperate to promote cancer progression and therapeutic resistance. mTOR inhibitors induce growth suppression and death receptor/FADD-dependent apoptosis in colon cancer cells and xeno-grafts. Using a panel of BRAFV600E 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 BRAFV600E-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 pERK/Mcl-1 elevation 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.