ArticleNature biotechnology2022
Ras-mutant cancers are sensitive to small molecule inhibition of V-type ATPases in mice.
Article in Nature biotechnology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
24 citing papers in PubMed, 36 citations in OpenAlex.
- Recent progress in small molecules targeting the acidic tumor microenvironment.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Compartmental pH regulation in cancer and antitumor immunity: therapeutic opportunities and challenges.Apoptosis : an international journal on programmed cell death · 2026Review
- DS96432529 enhances osteogenic differentiation and mitigates inflammatory damage in periodontal ligament stem cells involving mitophagy-related processes.Stem cell research & therapy · 2026Article
- ELOVL6 activity attenuation induces mutant KRAS degradation.Nature chemical biology · 2026Article
- Innovative Therapies for Oncogenic KRAS Mutations: Precision Strategies with PROTACs in Cancer Treatment.Anti-cancer agents in medicinal chemistry · 2026Review
- BOGO: A Proteome-Wide Gene Overexpression Platform for Discovering Rational Cancer Combination Therapies.bioRxiv : the preprint server for biology · 2025Article
- Acidic Tumor Microenvironments and Emerging Therapeutic Strategies for Cancer Therapy.Yonsei medical journal · 2025Review
- Review
- Nanomedicine Approaches for Autophagy Modulation in Cancer Therapy.Small science · 2025Article
- Autophagy controls neuronal differentiation by regulating the WNT-DVL signaling pathway.Autophagy · 2025Article
- Targeting secretory autophagy in solid cancers: mechanisms, immune regulation and clinical insights.Experimental hematology & oncology · 2025Review
- V-ATPase in cancer: mechanistic insights and therapeutic potentials.Cell communication and signaling : CCS · 2024Review
- Emerging Targets in Non-Small Cell Lung Cancer.International journal of molecular sciences · 2024Review
- Ferroptosis: principles and significance in health and disease.Journal of hematology & oncology · 2024Review
- Targeting RAF dimers in RAS mutant tumors: From biology to clinic.Acta pharmaceutica Sinica. B · 2024Review
- A pH Fingerprint Assay to Identify Inhibitors of Multiple Validated and Potential Antimalarial Drug Targets.ACS infectious diseases · 2024Article
- Targeting KRAS mutations in pancreatic cancer: opportunities for future strategies.Frontiers in medicine · 2024Review
- Honokiol enhances the sensitivity of cetuximab in KRASTheranostics · 2024Article
- New Developments in Treating RAS-Mutated Metastatic Colorectal Cancer.Current treatment options in oncology · 2023Review
- RAS and Other Molecular Targets in Pancreatic Cancer: The Next Wave Is Coming.Current treatment options in oncology · 2023Review
Corrections and comments
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Authors and funding
14 authors at 6 institutions in 3 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.