Back to Search
Start Over
Modulation of Bax and mTOR for Cancer Therapeutics.
- Source :
-
Cancer research [Cancer Res] 2017 Jun 01; Vol. 77 (11), pp. 3001-3012. Date of Electronic Publication: 2017 Apr 05. - Publication Year :
- 2017
-
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 .<br /> (©2017 American Association for Cancer Research.)
- Subjects :
- Animals
Cell Line, Tumor
Cell Proliferation
Disease Models, Animal
Humans
Lung Neoplasms pathology
Mice
Models, Structural
Phosphorylation
Signal Transduction
Lung Neoplasms genetics
TOR Serine-Threonine Kinases genetics
TOR Serine-Threonine Kinases metabolism
bcl-2-Associated X Protein genetics
bcl-2-Associated X Protein metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1538-7445
- Volume :
- 77
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Cancer research
- Publication Type :
- Academic Journal
- Accession number :
- 28381544
- Full Text :
- https://doi.org/10.1158/0008-5472.CAN-16-2356