Abstract 2333: Modulation of Bax and mTOR for cancer therapeutics

Pharmacologic manipulation of the serine (S)184 phosphorylation site of Bax protein to functionally regulate its proapoptotic activity is an attractive anticancer strategy. We recently identified three small molecule Bax agonists. SMBA1 was selected as the lead compound based on its chemical structure and its drug-like properties, from which a more effective analog, CYD-2-11, was generated. CYD-2-11 targets the structural pocket around S184 in the C-terminal tail of Bax, directly activating its proapoptotic activity via 6A7 conformational change and formation of Bax homo-oligomers in mitochondrial membranes. CYD-2-11 suppresses tumor growth in SCLC, NSCLC and patient-derived lung cancer xenografts as well as the genetically engineered mutant KRAS-driven lung cancer model with no significant normal tissue toxicity. Inhibition of mTOR by RAD001 enhances S184 Bax phosphorylation in lung cancer cell lines and tumor tissues from lung cancer patients treated with RAD001, which inactivates the propaoptotic function of Bax, contributing to rapalog-resistance. Combined CYD-2-11 and RAD001 treatment not only displays strong synergistic activity against lung cancer but also overcomes rapalog-resistance in vitro and in vivo. Therefore, a mechanism-driven combination of Bax agonist and mTOR inhibitor represents a highly attractive therapeutic strategy to improve lung cancer patient outcomes. Citation Format: Rui Li, Chunyong Ding, Jun Zhang, Maohua Xie, Dongkyoo Park, Ye Ding, Guo Chen, Guojing Zhang, Melissa Gilbert-Ross, Wei Zhou, Adam Marcus, Shi-Yong Sun, Zhuo Chen, Gabriel Sica, Suresh Ramalingam, Andrew Magis, Haian Fu, Fadlo Khuri, Walter Curran, Taofeek Owonikoko, Dong Shin, Jia Zhou, Xingming Deng. Modulation of Bax and mTOR for cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2333. doi:10.1158/1538-7445.AM2017-2333