Modulation of Bax and mTOR for Cancer Therapeutics.
Modulation of Bax and mTOR for Cancer Therapeutics.
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DOI：
10.1158/0008-5472.can-16-2356
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发表时间：
2017-06-01
期刊：
影响因子：
11.2
通讯作者：
Deng X
中科院分区：
文献类型：
--
作者：
Li R;Ding C;Zhang J;Xie M;Park D;Ding Y;Chen G;Zhang G;Gilbert-Ross M;Zhou W;Marcus AI;Sun SY;Chen ZG;Sica GL;Ramalingam SS;Magis AT;Fu H;Khuri FR;Curran WJ;Owonikoko TK;Shin DM;Zhou J;Deng X
A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small cell and non-small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 suppressed malignant growth without evident significant toxicity to normal tissues. In lung cancer patients treated with mTOR inhibitor RAD001, we observed enhanced S184 Bax phosphorylation in lung cancer cells and tissues which inactivates the propaoptotic function of Bax, contributing to rapalog resistance. Combined treatment of CYD-2-11 and RAD001 in murine lung cancer models displayed strong synergistic activity and overcame rapalog resistance in vitro and in vivo. Taken together, our findings provide preclinical evidence for a pharmacologic combination of Bax activation and mTOR inhibition as a rational strategy to improve lung cancer treatment.
