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mTORC1-Driven Tumor Cells Are Highly Sensitive to Therapeutic Targeting by Antagonists of Oxidative Stress
Jing Li1, Sejeong Shin2, Yang Sun3
1Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
Abstract:
mTORC1 is a central signaling node in controlling cell growth, proliferation, and metabolism that is aberrantly activated in cancers and certain cancer-associated genetic disorders, such as tuberous sclerosis complex (TSC) and sporadic lymphangioleiomyomatosis. However, while mTORC1-inhibitory compounds (rapamycin and rapalogs) attracted interest as candidate therapeutics, clinical trials have not replicated the promising findings in preclinical models, perhaps because these compounds tend to limit cell proliferation without inducing cell death. In seeking to address this issue, we performed a high-throughput screen for small molecules that could heighten the cytotoxicity of mTORC1 inhibitors. Here we report the discovery that combining inhibitors of mTORC1 and glutamate cysteine ligase (GCLC) can selectively and efficiently trigger apoptosis in Tsc2-deficient cells but not wild-type cells. Mechanistic investigations revealed that coinhibition of mTORC1 and GCLC decreased the level of the intracellular thiol antioxidant glutathione (GSH), thereby increasing levels of reactive oxygen species, which we determined to mediate cell death in Tsc2-deficient cells. Our findings offer preclinical proof of concept for a strategy to selectively increase the cytotoxicity of mTORC1 inhibitors as a therapy to eradicate tumor cells marked by high mTORC1 signaling, based on cotargeting a GSH-controlled oxidative stress pathway. Cancer Res; 76(16); 4816-27. ©2016 AACR.
Insights
Combining mTORC1 and glutamate cysteine ligase (GCLC) inhibitors triggers cancer cell death by increasing oxidative stress. This strategy selectively targets Tsc2-deficient cells, offering a new therapeutic approach for cancers with high mTORC1 signaling.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- The mechanistic target of rapamycin complex 1 (mTORC1) pathway is crucial for cell growth and metabolism, and its aberrant activation is implicated in various cancers and genetic disorders like tuberous sclerosis complex (TSC).
- Current mTORC1 inhibitors (rapamycin and rapalogs) show limited clinical efficacy, potentially due to their inability to induce cancer cell death, primarily limiting proliferation.
- A strategy to enhance the cytotoxicity of mTORC1 inhibitors is needed to effectively treat cancers characterized by hyperactive mTORC1 signaling.
Purpose of the Study:
- To identify small molecules that can potentiate the cancer cell-killing effects of mTORC1 inhibitors.
- To investigate the combined efficacy and mechanism of action of mTORC1 and glutamate cysteine ligase (GCLC) inhibition in cancer cells.
Main Methods:
- High-throughput screening for compounds that enhance the cytotoxicity of mTORC1 inhibitors.
- Co-inhibition of mTORC1 and GCLC in Tsc2-deficient and wild-type cancer cells.
- Measurement of intracellular glutathione (GSH) levels and reactive oxygen species (ROS).
- Assessment of apoptosis induction in treated cells.
Main Results:
- The combination of mTORC1 and GCLC inhibitors selectively induced apoptosis in Tsc2-deficient cancer cells, but not in wild-type cells.
- This co-inhibition led to a significant decrease in intracellular glutathione (GSH) levels.
- The reduction in GSH resulted in increased reactive oxygen species (ROS) production, which mediated cancer cell death.
Conclusions:
- Co-targeting mTORC1 and GCLC represents a promising preclinical strategy to selectively enhance the cytotoxicity of mTORC1 inhibitors.
- This approach leverages the targeting of a glutathione (GSH)-controlled oxidative stress pathway to eradicate tumor cells with high mTORC1 signaling.
- The findings provide a proof-of-concept for a novel therapeutic strategy against specific cancer types.
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