Modulation of Bax and mTOR for Cancer Therapeutics

作者：Li Rui; Ding Chunyong; Zhang Jun; Xie Maohua; Park Dongkyoo; Ding Ye; Chen Guo; Zhang Guojing; Gilbert Ross Melissa; Zhou Wei; Marcus Adam I; Sun Shi Yong; Chen Zhuo G; Sica Gabriel L; Ramalingam Suresh S; Magis Andrew T; Fu Haian; Khuri Fadlo R; Curran Walter J; Owonikoko Taofeek K; Shin Dong M^*; Zhou Jia^*; Deng Xingming^*

来源：Cancer Research, 2017, 77(11): 3001-3012.

DOI：10.1158/0008-5472.CAN-16-2356

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 mod-els, 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 that 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.

• 出版日期2017-6-1