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Ref Type Journal Article
PMID (36922589)
Authors Perner F, Stein EM, Wenge DV, Singh S, Kim J, Apazidis A, Rahnamoun H, Anand D, Marinaccio C, Hatton C, Wen Y, Stone RM, Schaller D, Mowla S, Xiao W, Gamlen HA, Stonestrom AJ, Persaud S, Ener E, Cutler JA, Doench JG, McGeehan GM, Volkamer A, Chodera JD, Nowak RP, Fischer ES, Levine RL, Armstrong SA, Cai SF
Title MEN1 mutations mediate clinical resistance to menin inhibition.
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Revumenib Revumenib 3 8
Drug Name Trade Name Synonyms Drug Classes Drug Description
Revumenib SNDX5613|SNDX 5613|SNDX-5613 MEN1-KMT2A Inhibitor 7 Revumenib (SNDX-5613) inhibits the interaction between Menin and KMT2A (MLL), potentially resulting in antitumor activity and decreased proliferation of tumor cells with KMT2A (MLL) rearrangements or NPM1 mutations (PMID: 36922593, PMID: 36922589).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KMT2A rearrange acute myeloid leukemia predicted - sensitive Revumenib Case Reports/Case Series Actionable In a Phase I trial (AUGMENT-101), Revumenib treatment resulted in an initial response with morphological leukemia-free states in 2 patients with acute myeloid leukemia harboring KMT2A rearrangements (PMID: 36922589; NCT04065399). 36922589