Modulation of Bax and mTOR for Cancer Therapeutics

• Type of Material: Article
• Authors: Rui Li, Emory University; Chunyong Ding, University of Texas; Jun Zhang, Emory University; Maohua Xie, Emory University; Dongkyoo Park, Emory University; Ye Ding, University of Texas; Guo Chen, Emory University; Guojing Zhang, Emory University; Melissa Gilbert-Ross, Emory University; Wei Zhou, Emory University; Adam I Marcus, Emory University; Shi-Yong Sun, Emory University; Zhuo G. Chen, Emory University; Gabriel Sica, Emory University; Suresh S Ramalingam, Emory University; Andrew T. Magis, Institute for Systems Biology; Haian Fu, Emory University; Fadlo Khuri, Emory University; Walter J Curran, Emory University; Taofeek K Owonikoko, Emory University; Dong M Shin, Emory University; Jia Zhou, University of Texas; Xingming Deng, Emory University
• Language: English
• Date: 2017-04-05
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2017 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-16-2356
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 77
• Issue: 11
• Start Page: 3001
• End Page: 3012
• Grant/Funding Information: The costs of publication of this article were defrayed in part by the payment of page charges.; This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.; This work was supported by National Institutes of Health grants 2R01CA136534-06 (X. Deng), R01CA193828 (X. Deng), 1R01CA200905-01A1 (X. Deng), R01CA140571 (W. Zhou), P50 CA097007 (J. Zhou), P30 DA028821 (J. Zhou) and T32CA160040 (D.M. Shin) as well as R. A. Welch Foundation Chemistry and Biology Collaborative Grant from Gulf Coast Consortia (GCC) for Chemical Genomics, Cancer Prevention and Research Institute of Texas (CPRIT) awards (J. Zhou), and John Sealy Memorial Endowment Fund (J. Zhou).; Research reported in this publication was also supported in part by by the Winship Research Pathology and Intergrated Cellular Imaging shared resource, the cores supported by the Winship Cancer Institute of Emory University (P30CAJ 38292), and by the Winship Fashion a Cure Research Scholar Award (X. Deng), a philanthropic award provided by the Winship Cancer Institute of Emory University.
• Keywords: CELL LUNG-CANCER; APOPTOSIS; Life Sciences & Biomedicine; PROAPOPTOTIC FUNCTION; MAMMALIAN TARGET; MODELS; PHASE-II; INHIBITION; EVEROLIMUS RAD001; Science & Technology; THERAPY; BCL-XL; Oncology
• Research Categories: Health Sciences, Pathology; Health Sciences, Pharmacology; Health Sciences, Oncology

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.