Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice
Bhairavi Tolani1, Anna Celli2, Yanmin Yao3
1Thoracic Oncology Program, Department of Surgery, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA. Bhairavi.Tolani@ucsf.edu.
Abstract:
Mutations in Ras family proteins are implicated in 33% of human cancers, but direct pharmacological inhibition of Ras mutants remains challenging. As an alternative to direct inhibition, we screened for sensitivities in Ras-mutant cells and discovered 249C as a Ras-mutant selective cytotoxic agent with nanomolar potency against a spectrum of Ras-mutant cancers. 249C binds to vacuolar (V)-ATPase with nanomolar affinity and inhibits its activity, preventing lysosomal acidification and inhibiting autophagy and macropinocytosis pathways that several Ras-driven cancers rely on for survival. Unexpectedly, potency of 249C varies with the identity of the Ras driver mutation, with the highest potency for KRASG13D and G12V both in vitro and in vivo, highlighting a mutant-specific dependence on macropinocytosis and lysosomal pH. Indeed, 249C potently inhibits tumor growth without adverse side effects in mouse xenografts of KRAS-driven lung and colon cancers. A comparison of isogenic SW48 xenografts with different KRAS mutations confirmed that KRASG13D/+ (followed by G12V/+) mutations are especially sensitive to 249C treatment. These data establish proof-of-concept for targeting V-ATPase in cancers driven by specific KRAS mutations such as KRASG13D and G12V.
Insights
A novel agent, 249C, selectively targets Ras-mutant cancers by inhibiting vacuolar (V)-ATPase. This discovery offers a new therapeutic strategy for specific KRAS mutations, showing promise in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Ras family proteins are frequently mutated in human cancers, presenting a therapeutic challenge.
- Directly inhibiting Ras mutants pharmacologically is difficult, necessitating alternative strategies.
Purpose of the Study:
- To identify novel therapeutic agents targeting Ras-mutant cancers.
- To investigate the mechanism of action and efficacy of the identified agent, 249C.
Main Methods:
- Screening of Ras-mutant cells for drug sensitivities.
- Biochemical assays to determine the target and mechanism of 249C.
- In vitro and in vivo studies using cancer cell lines and mouse xenografts.
Main Results:
- 249C identified as a Ras-mutant selective cytotoxic agent with nanomolar potency.
- 249C binds to and inhibits vacuolar (V)-ATPase, impacting lysosomal acidification, autophagy, and macropinocytosis.
- Potency of 249C is dependent on the specific Ras mutation, with highest efficacy against KRAS G13D and G12V.
- 249C demonstrated potent tumor growth inhibition in KRAS-driven lung and colon cancer xenografts with no observed adverse effects.
Conclusions:
- 249C is a potent V-ATPase inhibitor effective against specific KRAS-mutant cancers.
- Targeting V-ATPase represents a viable therapeutic approach for KRAS G13D and G12V-driven tumors.
- The mutant-specific efficacy highlights the potential for personalized cancer therapy.
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