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MEN1 mutations mediate clinical resistance to menin inhibition

Author

Listed:
  • Florian Perner

    (Boston Children’s Hospital and Harvard Medical School
    University Medicine Greifswald)

  • 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
    Harvard Medical School)

  • 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
    University Medicine Greifswald)

  • 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
    Memorial Sloan Kettering Cancer Center)

  • Holly A. Gamlen

    (Memorial Sloan Kettering Cancer Center)

  • Aaron J. Stonestrom

    (Memorial Sloan Kettering Cancer Center
    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
    Harvard Medical School)

  • Eric S. Fischer

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Ross L. Levine

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

  • Scott A. Armstrong

    (Boston Children’s Hospital and Harvard Medical School)

  • Sheng F. Cai

    (Memorial Sloan Kettering Cancer Center
    Memorial Sloan Kettering Cancer Center)

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.

Suggested Citation

  • 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. Sto, 2023. "MEN1 mutations mediate clinical resistance to menin inhibition," Nature, Nature, vol. 615(7954), pages 913-919, March.
  • Handle: RePEc:nat:nature:v:615:y:2023:i:7954:d:10.1038_s41586-023-05755-9
    DOI: 10.1038/s41586-023-05755-9
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    Cited by:

    1. Derek H. Janssens & Melodie Duran & Dominik J. Otto & Weifang Wu & Yiling Xu & Danielle Kirkey & Charles G. Mullighan & Joanna S. Yi & Soheil Meshinchi & Jay F. Sarthy & Kami Ahmad & Steven Henikoff, 2024. "MLL oncoprotein levels influence leukemia lineage identities," Nature Communications, Nature, vol. 15(1), pages 1-13, December.

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