MEN1 mutations mediate clinical resistance to menin inhibition

Florian Perner, Eytan M. Stein, Daniela V. Wenge, Sukrit Singh, Jeonghyeon Kim, Athina Apazidis, Homa Rahnamoun, Disha Anand, Christian Marinaccio, Charlie Hatton, Yanhe Wen, Richard M. Stone, David Schaller, Shoron Mowla, Wenbin Xiao, Holly A. Gamlen, Aaron J. Stonestrom, Sonali Persaud, Elizabeth Ener, Jevon A. Cutler, John G. Doench, Gerard M. McGeehan, Andrea Volkamer, John D. Chodera, Radosław P. Nowak, Eric S. Fischer, Ross L. Levine (), Scott A. Armstrong () and Sheng F. Cai ()
Additional contact information
Florian Perner: Boston Children’s Hospital and Harvard Medical School
Eytan M. Stein: Memorial Sloan Kettering Cancer Center
Daniela V. Wenge: Boston Children’s Hospital and Harvard Medical School
Sukrit Singh: Memorial Sloan Kettering Cancer Center
Jeonghyeon Kim: Dana-Farber Cancer Institute
Athina Apazidis: Boston Children’s Hospital and Harvard Medical School
Homa Rahnamoun: Boston Children’s Hospital and Harvard Medical School
Disha Anand: Boston Children’s Hospital and Harvard Medical School
Christian Marinaccio: Boston Children’s Hospital and Harvard Medical School
Charlie Hatton: Boston Children’s Hospital and Harvard Medical School
Yanhe Wen: Boston Children’s Hospital and Harvard Medical School
Richard M. Stone: Dana-Farber Cancer Institute
David Schaller: Charité-Universitätsmedizin Berlin
Shoron Mowla: Memorial Sloan Kettering Cancer Center
Wenbin Xiao: Memorial Sloan Kettering Cancer Center
Holly A. Gamlen: Memorial Sloan Kettering Cancer Center
Aaron J. Stonestrom: Memorial Sloan Kettering Cancer Center
Sonali Persaud: Memorial Sloan Kettering Cancer Center
Elizabeth Ener: Boston Children’s Hospital and Harvard Medical School
Jevon A. Cutler: Boston Children’s Hospital and Harvard Medical School
John G. Doench: Broad Institute
Gerard M. McGeehan: Syndax Pharmaceuticals
Andrea Volkamer: Charité-Universitätsmedizin Berlin
John D. Chodera: Memorial Sloan Kettering Cancer Center
Radosław P. Nowak: Dana-Farber Cancer Institute
Eric S. Fischer: Dana-Farber Cancer Institute
Ross L. Levine: Memorial Sloan Kettering Cancer Center
Scott A. Armstrong: Boston Children’s Hospital and Harvard Medical School
Sheng F. Cai: Memorial Sloan Kettering Cancer Center

Nature, 2023, vol. 615, issue 7954, 913-919

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-05755-9

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