2. Academic Validation
  3. Modulation of Bax and mTOR for Cancer Therapeutics

Modulation of Bax and mTOR for Cancer Therapeutics

  • Cancer Res. 2017 Jun 1;77(11):3001-3012. doi: 10.1158/0008-5472.CAN-16-2356.
Rui Li 1,  Chunyong Ding 2,  Jun Zhang 3,  Maohua Xie 1,  Dongkyoo Park 1,  Ye Ding 2,  Guo Chen 1,  Guojing Zhang 3,  Melissa Gilbert-Ross 3,  Wei Zhou 3,  Adam I Marcus 3,  Shi-Yong Sun 3,  Zhuo G Chen 3,  Gabriel L Sica 4,  Suresh S Ramalingam 3,  Andrew T Magis 5,  Haian Fu 3,  Fadlo R Khuri 3,  Walter J Curran 1,  Taofeek K Owonikoko 3,  Dong M Shin 6,  Jia Zhou 7,  Xingming Deng 8
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
  • 2 Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas.
  • 3 Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
  • 4 Department of Pathology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
  • 5 Institute for Systems Biology, Seattle, Washington.
  • 6 Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia. [email protected] [email protected] [email protected].
  • 7 Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas. [email protected] [email protected] [email protected].
  • 8 Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia. [email protected] [email protected] [email protected].
PMID: 28381544 DOI: 10.1158/0008-5472.CAN-16-2356
Abstract

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 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. Cancer Res; 77(11); 3001-12. ©2017 AACR.

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