MEN1 mutations mediate clinical resistance to menin inhibition

Nature. 2023 Mar;615(7954):913-919. doi: 10.1038/s41586-023-05755-9. Epub 2023 Mar 15.

Abstract

Chromatin-binding proteins are critical regulators of cell state in haematopoiesis1,2. Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs3-5. In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin-MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref. 6). Here we identified somatic mutations in MEN1 at the revumenib-menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor-menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug-target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Binding Sites / drug effects
  • Binding Sites / genetics
  • Chromatin / genetics
  • Chromatin / metabolism
  • Drug Resistance, Neoplasm* / genetics
  • Humans
  • Leukemia* / drug therapy
  • Leukemia* / genetics
  • Leukemia* / metabolism
  • Mutation*
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins* / antagonists & inhibitors
  • Proto-Oncogene Proteins* / chemistry
  • Proto-Oncogene Proteins* / genetics
  • Proto-Oncogene Proteins* / metabolism

Substances

  • Antineoplastic Agents
  • Chromatin
  • KMT2A protein, human
  • MEN1 protein, human
  • NPM1 protein, human
  • Proto-Oncogene Proteins