MEN1 mutations mediate clinical resistance to menin inhibition

Chromatin-binding proteins are critical regulators of cell state in haematopoiesis 1 , 2 . Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene ( KMT2A r) or mutation of the nucleophosmin gene ( NPM1 ) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs 3 – 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 KMT2A r 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.