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Multiselective RAS(ON) inhibition targets oncogenic RAS and overcomes RAS-mediated resistance to FLT3i and BCL2i in

Bogdan Popescu1, Matthew F Jones1, Madison Piao1

  • 1Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA.

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Summary
This summary is machine-generated.

A new drug, RMC-7977, shows promise in treating acute myeloid leukemia (AML) by targeting RAS signaling. This multi-selective RAS inhibitor effectively overcomes resistance to existing therapies like FLT3 inhibitors and venetoclax in preclinical AML models.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Aberrant RAS/MAPK signaling is a key mechanism limiting targeted therapy efficacy in acute myeloid leukemia (AML).
  • RAS mutations drive resistance to FLT3 inhibitors (FLT3i) and venetoclax in AML, representing a significant unmet clinical need.
  • Currently, no targeted therapies specifically targeting RAS-driven AML have shown clinical benefit.

Purpose of the Study:

  • To investigate the preclinical activity of RMC-7977, a novel multi-selective inhibitor of GTP-bound active [RAS(ON)] isoforms.
  • To evaluate RMC-7977's potential to overcome resistance to FLT3 inhibitors and venetoclax in AML models.
  • To assess the combination efficacy of RMC-7977 with existing AML therapies in preclinical models.

Main Methods:

  • Screening of RMC-7977 across AML cell lines with various MAPK-activating signaling mutations.
  • Assessment of RMC-7977's ability to restore sensitivity to FLT3i in cell lines with acquired resistance due to RAS mutations.
  • Evaluation of RMC-7977's effect on venetoclax resistance in RAS-addicted AML cell line models.
  • Testing RMC-7977 in combination with gilteritinib or venetoclax in murine patient-derived xenograft models of RAS-mutant AML.

Main Results:

  • RMC-7977 demonstrated potent antiproliferative and pro-apoptotic activity in AML cell lines with MAPK-activating mutations.
  • RMC-7977 restored sensitivity to FLT3 inhibitors in AML models with acquired resistance mediated by secondary RAS mutations.
  • RMC-7977 reversed venetoclax resistance in both RAS wild-type and mutant AML cell line models.
  • In vivo, RMC-7977 was well tolerated and significantly suppressed leukemic burden in combination regimens.

Conclusions:

  • Broad-spectrum RAS(ON) inhibition with RMC-7977 is a promising therapeutic strategy for AML.
  • RMC-7977 effectively overcomes resistance mechanisms associated with RAS activation in AML.
  • Clinical investigation of RMC-7977 is strongly supported to treat and prevent drug resistance in RAS-driven AML.