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Multi-selective RAS(ON) Inhibition Targets Oncogenic RAS Mutations and Overcomes RAS/MAPK-Mediated Resistance to FLT3

Bogdan Popescu1, Matthew F Jones1, Madison Piao1

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|July 15, 2025
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Summary
This summary is machine-generated.

A novel drug, RMC-7977, targets RAS activation in acute myeloid leukemia (AML). This RAS inhibitor overcomes resistance to FLT3 inhibitors and venetoclax, showing promise for AML treatment.

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Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Aberrant RAS/MAPK signaling drives resistance to targeted therapies in acute myeloid leukemia (AML).
  • RAS mutations confer resistance to FLT3 inhibitors (FLT3i) and venetoclax in AML.
  • Targeting RAS/MAPK signaling is crucial for improving AML treatment efficacy.

Purpose of the Study:

  • To investigate the preclinical efficacy of RMC-7977, a novel inhibitor of active RAS(ON) isoforms.
  • To evaluate RMC-7977's ability to overcome resistance to FLT3i and venetoclax in AML models.
  • To assess RMC-7977's safety and efficacy in combination with existing AML therapies.

Main Methods:

  • Preclinical evaluation of RMC-7977 in AML cell lines with MAPK-activating mutations.
  • Assessment of RMC-7977's effect on drug-resistant AML models (FLT3i-resistant and venetoclax-resistant).
  • In vivo studies using murine patient-derived xenograft models of RAS-mutant AML.

Main Results:

  • RMC-7977 demonstrated potent antiproliferative and pro-apoptotic activity in AML cell lines.
  • RMC-7977 restored sensitivity to FLT3i in models with acquired RAS-mediated resistance.
  • RMC-7977 reversed venetoclax resistance in RAS-addicted AML models.
  • Combination therapy with RMC-7977 and gilteritinib or venetoclax suppressed leukemic burden in vivo.

Conclusions:

  • RMC-7977 exhibits significant preclinical activity against RAS-driven AML.
  • Broad-spectrum RAS(ON) inhibition is a promising strategy to overcome drug resistance in AML.
  • Clinical investigation of RMC-7977 is warranted for AML treatment.