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Modulation of Bax and mTOR for Cancer Therapeutics
Rui Li1, Chunyong Ding2, Jun Zhang3
1Department 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.
Insights
Researchers developed CYD-2-11, a Bax agonist, to activate its cancer-fighting function. This drug, combined with an mTOR inhibitor, shows promise in overcoming lung cancer resistance and improving treatment outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- The proapoptotic protein Bax plays a crucial role in cancer cell death.
- Phosphorylation at serine 184 (S184) of Bax can inactivate its proapoptotic function.
- Targeting Bax phosphorylation presents a potential anticancer strategy.
Purpose of the Study:
- To refine a Bax agonist (SMBA1) into a clinical lead compound (CYD-2-11).
- To evaluate CYD-2-11's efficacy in preclinical lung cancer models.
- To investigate the combination of CYD-2-11 with mTOR inhibition to overcome treatment resistance.
Main Methods:
- Development and characterization of the Bax agonist CYD-2-11.
- Assessment of CYD-2-11 in murine models of small-cell and non-small cell lung cancer.
- Evaluation of combined treatment with CYD-2-11 and the mTOR inhibitor RAD001.
- Analysis of S184 Bax phosphorylation in response to RAD001 treatment.
Main Results:
- CYD-2-11 directly activated Bax's proapoptotic activity by inducing conformational changes and homooligomerization.
- CYD-2-11 suppressed tumor growth in various lung cancer models with minimal toxicity.
- Enhanced S184 Bax phosphorylation was observed in lung cancer cells treated with RAD001, contributing to resistance.
- Combined CYD-2-11 and RAD001 treatment demonstrated synergistic activity and overcame resistance both in vitro and in vivo.
Conclusions:
- CYD-2-11 is a promising clinical lead compound for Bax activation therapy.
- Pharmacologic Bax activation combined with mTOR inhibition offers a rational strategy to improve lung cancer treatment.
- This combination approach may overcome resistance to existing therapies like rapalogs.