Multiselective RAS(ON) inhibition targets oncogenic RAS and overcomes RAS-mediated resistance to FLT3i and BCL2i in AML
Abstract
Abstract Aberrant activation of RAS/MAPK signaling limits the clinical efficacy of several targeted therapies in acute myeloid leukemia (AML). In FMS-like tyrosine kinase-3 (FLT3)-mutant AML, the selection of clones harboring heterogeneous RAS mutations drives resistance to FLT3 inhibitors (FLT3i). RAS activation is also associated with resistance to other AML targeted therapies, such as the B-cell lymphoma 2 inhibitor venetoclax. Despite the critical need to inhibit RAS/MAPK signaling in AML, no targeted therapies have demonstrated a clinical benefit in RAS-driven AML. To address this unmet need, we investigated the preclinical activity of RMC-7977, a multiselective inhibitor of GTP-bound active (RAS[ON]) isoforms of mutant and wild-type RAS in AML models. RMC-7977 exhibited potent antiproliferative and proapoptotic activity across AML cell lines with MAPK-activating signaling mutations. In cell line models with acquired FLT3i resistance because of secondary RAS mutations, treatment with RMC-7977 restored sensitivity to FLT3i. Similarly, RMC-7977 effectively reversed resistance to venetoclax in RAS-addicted cell line models with both RAS wild-type and mutant genetic backgrounds. In murine patient-derived xenograft models of RAS-mutant AML, RMC-7977 was well tolerated and significantly suppressed leukemic burden in combination with gilteritinib or venetoclax. Our findings strongly support clinical investigation of broad-spectrum RAS(ON) inhibition in AML to treat and potentially prevent drug resistance because of activated RAS signaling.
Article Details
Authors (19)
Bogdan Popescu
University of California San Francisco, San Francisco, California, United States
Matthew F. Jones
1Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA
Madison Piao
1Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA
Elaine Tran
University of California San Francisco, San Francisco, California, United States
Andrew Koh
Isabelle Lomeli
University of California San Francisco, San Francisco, California, United States
Cheryl A. C. Peretz
University of California San Francisco, San Francisco, California, United States
Natalia Murad
University of California San Francisco, San Francisco, California, United States
Sydney Abelson
Carolina Morales
Jose M. Rivera
Benioff Children's Hospital, University of California, San Francisco, San Francisco, California, United States
Alexa Rane Batingana
2Division of Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, CA
Jeevitha D’Souza
2Division of Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, CA
Yana Pikman
Michael L. Cheng
1Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA
Aaron C. Logan
19Department of Medicine, University of California San Francisco, San Francisco, CA
Benjamin J. Huang
2Division of Oncology, Department of Pediatrics, University of California San Francisco, San Francisco, CA
Elliot Stieglitz
Catherine C. Smith
University of California (San Francisco), San Francisco, California, United States