Modulation of Bax and mTOR for Cancer Therapeutics
Authors: Maohua Xie
Ye Ding
Dongkyoo Park
Haian Fu
Guojing Zhang
Rui Li
Suresh S Ramalingam
Walter J Curran
Xingming Deng
Jia Zhou
Adam I Marcus
Wei Zhou
Gabriel L Sica
Andrew T Magis
Shi-Yong Sun
Jun Zhang
Guo Chen
Chunyong Ding
Dong M Shin
Zhuo G Chen
Taofeek K Owonikoko
Melissa Gilbert-Ross
Fadlo R Khuri
Journal: Cancer Research (2017)
Discipline: CLINICAL MEDICINE
Keywords: pharmacologic manipulation; serine phosphorylation; Bax agonist; CYD-2-11; proapoptotic activity
Affiliations: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia., Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas., Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia., Department of Pathology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia., Institute for Systems Biology, Seattle, Washington., Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.   ., Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas.   ., Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.   .

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. 

Retracted: No

PubPeer comments:
 Figure 7B appears to have two images which overlap. Roughly indicated by cyan box. I believe this carries through the whole row, but I did not annotate that. Apologies if Iu2019m misunderstanding something. *** ![file] *** ![file] , 
 It s worth to note that the Merge panel in CYD 2-11 doesn t seem to be a merge, but the same image represented by DAPI , 
 To fix this error, I am contacting the first author Dr. Li who provided me Figure 7B . Sorry, I did not catch this mistake initially. Since she already left my laboratory and returned China long time ago. If I do not receive her response, I will ask my current lab member (another co-author) to repeat this experiment to obtain accurate data. Thank you for your great catching and valuable comments. I highly appreciate. , 
 #2 I believe you are right. #3 Dr. Deng: thank you for responding and good luck with your efforts. , 
 The authors do not seem to have addressed the above issues. Additionally, upon further analysis, Figure 2E and Figure 7C appear to have images which overlap. At this point and given the inability of the authors to recover the original data, perhaps a retraction is in order. *** 2E ![file] *** 7C ![file] , 
 We can recover original data. We will post corrected data next week! Thanks , 
 The corrected image of Figure 7B (two lower panels (CYD-2-11, RAD001+CYD-2-11) in left part) is attached as below. These corrections do not change any conclusions made in the article. ![file] , 
 The corrected image of Fig. 7C is attached as below. Fig. 2E has no problem. These corrections do not change any conclusions made in the article. ![file] , 
 #8 Thank you for preparing the new images. Is there an update on the correction? Do the new images affect Figure 7D? , 
 #9 The new images do not affect 7D. Thanks. ,