title: Modulation of Bax and mTOR for Cancer Therapeutics.
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 resistancein vitroandin vivoTaken 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.
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Chunyong
authors.initials: C
authors.lastname: Ding
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Maohua
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Dongkyoo
authors.initials: D
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Ye
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Guo
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Guojing
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Gilbert-Ross
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Adam I
authors.initials: AI
authors.lastname: Marcus
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Shi-Yong
authors.initials: SY
authors.lastname: Sun
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Zhuo G
authors.initials: ZG
authors.lastname: Chen
authors.affiliation: Department of Pathology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Sica
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.affiliation: Institute for Systems Biology, Seattle, Washington.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Magis
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia.
authors.forename: Taofeek K
authors.initials: TK
authors.lastname: Owonikoko
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia. xdeng4@emory.edu jizhou@utmb.edu dmshin@emory.edu.
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.affiliation: Department of Pharmacology and Toxicology, Chemical Biology Program, University of Texas Medical Branch, Galveston, Texas. xdeng4@emory.edu jizhou@utmb.edu dmshin@emory.edu.
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine and Winship Cancer Institute of Emory University, Atlanta, Georgia. xdeng4@emory.edu jizhou@utmb.edu dmshin@emory.edu.
authors.forename: Xingming
authors.initials: X
authors.lastname: Deng
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008961:Models, Structural; D010766:Phosphorylation; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051028:bcl-2-Associated X Protein; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases