MEN1 mutations mediate clinical resistance to menin inhibition Journal Article
| Authors: | Perner, F.; Stein, E. M.; Wenge, D. V.; Singh, S.; Kim, J.; Apazidis, A.; Rahnamoun, H.; Anand, D.; Marinaccio, C.; Hatton, C.; Wen, Y.; Stone, R. M.; Schaller, D.; Mowla, S.; Xiao, W.; Gamlen, H. A.; Stonestrom, A. J.; Persaud, S.; Ener, E.; Cutler, J. A.; Doench, J. G.; McGeehan, G. M.; Volkamer, A.; Chodera, J. D.; Nowak, R. P.; Fischer, E. S.; Levine, R. L.; Armstrong, S. A.; Cai, S. F. |
| Article Title: | MEN1 mutations mediate clinical resistance to menin inhibition |
| 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. © 2023, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | cancer survival; clinical article; controlled study; human tissue; leukemia; unclassified drug; gene mutation; human cell; somatic mutation; genetics; mutation; cancer recurrence; cancer growth; nonhuman; antineoplastic agent; binding affinity; animal cell; mouse; animal tissue; multiple cycle treatment; gene expression; animal experiment; animal model; protein; transcription factor; evolution; cell differentiation; transcription factors; chromatin; leukemia cell; hydrogen bond; therapy resistance; leukemia relapse; drug binding; predictive value; inhibition; selection; cell; drug; acute myeloid leukemia; long term survival; humans; human; female; article; men1 gene; ic50; vtp 50469; menin (protein); revumenib |
| Journal Title: | Nature |
| Volume: | 615 |
| Issue: | 7954 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2023-03-30 |
| Start Page: | 913 |
| End Page: | 919 |
| Language: | English |
| DOI: | 10.1038/s41586-023-05755-9 |
| PUBMED: | 36922589 |
| PROVIDER: | scopus |
| PMCID: | PMC10157896 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF. Corresponding author is MSK authors Ross L. Levine and Sheng F. Cai -- Source: Scopus |
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