{"doi":"10.1038/s41375-021-01455-3","title":"Inhibition of the RacGEF VAV3 by the small molecule IODVA1 impedes RAC signaling and overcomes resistance to tyrosine kinase inhibition in acute lymphoblastic leukemia","abstract":"Abstract Aberrant RHO guanine nucleotide exchange factor (RhoGEF) activation is chief mechanism driving abnormal activation of their GTPase targets in transformation and tumorigenesis. Consequently, a small-molecule inhibitor of RhoGEF can make an anti-cancer drug. We used cellular, mouse, and humanized models of RAC-dependent BCR-ABL1-driven and Ph-like acute lymphoblastic leukemia to identify VAV3, a tyrosine phosphorylation–dependent RacGEF, as the target of the small molecule IODVA1. We show that through binding to VAV3, IODVA1 inhibits RAC activation and signaling and increases pro-apoptotic activity in BCR-ABL1-transformed cells. Consistent with this mechanism of action, cellular and animal models of BCR-ABL1-induced leukemia in Vav3 -null background do not respond to IODVA1. By durably decreasing in vivo RAC signaling, IODVA1 eradicates leukemic propagating activity of TKI-resistant BCR-ABL1(T315I) B-ALL cells after treatment withdrawal. Importantly, IODVA1 suppresses the leukemic burden in the treatment refractory pediatric Ph + and TKI-resistant Ph + B-ALL patient-derived xenograft models better than standard-of-care dasatinib or ponatinib and provides a more durable response after treatment withdrawal. Pediatric leukemia samples with diverse genetic lesions show high sensitivity to IODVA1 ex vivo and this sensitivity is VAV3 dependent. IODVA1 thus spearheads a novel class of drugs that inhibits a RacGEF and holds promise as an anti-tumor therapy.","journal":"Leukemia","year":2021,"id":192412,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9506,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":454175,"name":"Anjelika Gasilina","orcid":null,"position":1,"is_corresponding":false},{"id":108554,"name":"Mark Wunderlich","orcid":"0000-0002-2166-5146","position":2,"is_corresponding":false},{"id":701026,"name":"Yuan Lin","orcid":"0000-0002-4375-9805","position":3,"is_corresponding":false},{"id":759469,"name":"Marcel Buchholzer","orcid":"0000-0001-7485-6918","position":4,"is_corresponding":false},{"id":760164,"name":"Oliver H.F. Krumbach","orcid":null,"position":5,"is_corresponding":false},{"id":306620,"name":"Mohammad Akbarzadeh","orcid":null,"position":6,"is_corresponding":false},{"id":759470,"name":"Mohammad Reza Ahmadian","orcid":"0000-0002-2034-8894","position":7,"is_corresponding":false},{"id":362150,"name":"William Seibel","orcid":"0000-0003-1401-8618","position":8,"is_corresponding":false},{"id":333757,"name":"Yi Zheng","orcid":"0000-0001-7089-6074","position":9,"is_corresponding":false},{"id":295599,"name":"John P. Perentesis","orcid":"0000-0002-4237-8226","position":10,"is_corresponding":false},{"id":419919,"name":"Benjamin Mizukawa","orcid":"0000-0002-3312-2982","position":11,"is_corresponding":false},{"id":413463,"name":"Lisa M. Privette Vinnedge","orcid":"0000-0003-2087-4920","position":12,"is_corresponding":false},{"id":432590,"name":"José A. Cancelas","orcid":"0000-0002-1291-7233","position":13,"is_corresponding":false},{"id":453411,"name":"Nicolas Nassar","orcid":"0000-0003-0481-4784","position":14,"is_corresponding":false},{"id":416625,"name":"Shailaja Hegde","orcid":"0000-0001-8228-9570","position":0,"is_corresponding":true}],"reference_count":37,"raw_metadata":null,"created_at":"2026-07-18T23:49:43.496702Z","pmid":"34711926","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":[]}