{"doi":"10.1101/2020.12.23.423300","title":"Selective Targeting of Ras Mutant Cancers via a New Small Molecule","abstract":"ABSTRACT Mutations in the Ras family of oncogenes are implicated in 33% of human cancers, making Ras an intensely pursued target in drug discovery. As an alternative to direct pharmacological inhibition of Ras, we looked for sensitivities in RAS mutant cells. Using a small molecule screen in cell lines with mutations in Ras and its effector Raf, we discovered 249C as a Ras-mutant selective cytotoxic agent against a spectrum of RAS-mutant cancers. By combining CRISPR chemical-genetic screening, comparative profiling and chemoproteomics, we identified that 249C binds to a unique subunit on vacuolar (V)-ATPase with nanomolar affinity, inhibiting its biochemical activity and, unexpectedly, altering V-ATPase translocation in Ras-induced macropinocytosis. Via binding to V-ATPase, 249C prevents lysosomal acidification and inhibits autophagy and macropinocytosis pathways that several Ras-driven cancers rely on for survival. In characterizing 249C’s mechanism, we show that potency varies with the identity of the RAS driver mutation highlighting a mutant-specific dependence on autophagy and macropinocytosis. Indeed, 249C potently inhibits tumor growth without adverse side effects in a mouse xenograft model of KRAS -driven non-small cell lung cancer. These data establish proof-of-concept for targeting V-ATPase as a way to indirectly target specific Ras mutants, and provide a fundamental link between V-ATPase localization and specific Ras mutant tumor-related activity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":132059,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9434,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":587007,"name":"Anna Celli","orcid":"0000-0002-9692-8449","position":1,"is_corresponding":false},{"id":587509,"name":"Yanmin Yao","orcid":null,"position":2,"is_corresponding":false},{"id":355442,"name":"Yong Zi Tan","orcid":"0000-0001-6656-6320","position":3,"is_corresponding":false},{"id":314618,"name":"Richard D. Fetter","orcid":"0000-0002-1558-100X","position":4,"is_corresponding":false},{"id":289556,"name":"Christina R. Liem","orcid":"0000-0003-2744-6312","position":5,"is_corresponding":false},{"id":107666,"name":"Adam J. de Smith","orcid":"0000-0003-4880-7543","position":6,"is_corresponding":false},{"id":587008,"name":"Thamiya Vasanthakumar","orcid":"0000-0001-7172-0572","position":7,"is_corresponding":false},{"id":403046,"name":"Paola Bisignano","orcid":"0000-0003-1789-762X","position":8,"is_corresponding":false},{"id":272028,"name":"Ian B. Seiple","orcid":"0000-0002-8732-1362","position":9,"is_corresponding":false},{"id":587510,"name":"John L. Rubinstetin","orcid":null,"position":10,"is_corresponding":false},{"id":251069,"name":"Marco Jost","orcid":"0000-0002-1369-4908","position":11,"is_corresponding":false},{"id":17890,"name":"Jonathan S. Weissman","orcid":"0000-0003-2445-670X","position":12,"is_corresponding":false},{"id":587006,"name":"Bhairavi Tolani","orcid":"0000-0001-9076-866X","position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-18T23:16:07.542484Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}