CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials
Menin inhibitors have entered clinical trials for histone lysine methyltransferase 2 A (KMT2A)-rearranged and nucleophosmin 1 (NPM1)-mutant acute leukemias and are demonstrating promising activity. CRISPR base editor screening previously predicted several MEN1 (menin) mutations that have arisen in patients receiving SNDX-5613 and confer resistance. The extent to which MEN1 mutations will impact each menin inhibitor is mostly unknown. Here we show that CRISPR base editor screens can be leveraged to profile the MEN1 mutations that may impact five different menin inhibitors in clinical trials. We identify shared (M327I/V/T, G331D) and inhibitor-specific (C334R, E368K/V, V372A) resistance mutations. Co-crystal structures of menin bound to each menin inhibitor suggest resistance mechanisms related to how each inhibitor engages the KMT2A binding pocket of menin. Orthogonal in vitro and in vivo MEN1 mutation generation under therapeutic pressure suggest the MEN1 mutations identified with CRISPR base editor screening are likely to arise and impact all menin inhibitors.
Authors
- Shipra Bijpuria
- Jennifer A. Perry (ORCID: https://orcid.org/0000-0001-9328-1574)
- Daniela V. Wenge (ORCID: https://orcid.org/0000-0002-0064-9104)
- Sumaiya Iqbal (ORCID: https://orcid.org/0000-0001-7700-4374)
- Gerard M. McGeehan
- Hannah Rice (ORCID: https://orcid.org/0000-0001-6132-9334)
- Wallace Bourgeois (ORCID: https://orcid.org/0000-0002-6935-8890)
- Shivendra Singh (ORCID: https://orcid.org/0000-0002-4020-7255)
- Charlie Hatton (ORCID: https://orcid.org/0000-0001-9903-4291)
- Jevon Cutler (ORCID: https://orcid.org/0000-0002-3402-4292)
- Hong Yue (ORCID: https://orcid.org/0000-0003-4347-3193)
- Brian M. McKeever
- Florian Perner (ORCID: https://orcid.org/0000-0003-1010-3321)
- Alba Sommerschield
- Brandon Regalado
- Jordan Safer (ORCID: https://orcid.org/0009-0008-6007-7591)
- Sweta Singh (ORCID: https://orcid.org/0000-0002-3823-9477)
- William H. Miller (ORCID: https://orcid.org/0000-0002-4454-0987)
- George Wan
- Scott A. Armstrong (ORCID: https://orcid.org/0000-0002-9099-4728)
- John G. Doench (ORCID: https://orcid.org/0000-0002-3707-9889)
- Eric S. Fischer (ORCID: https://orcid.org/0000-0001-7337-6306)
- Jan C. Schroeder (ORCID: https://orcid.org/0000-0001-7000-4427)
Institutions
- Broad Institute (US)
- Nikon (United States) (US)
- Harvard University (US)
- Oregon Health & Science University (US)
- Medizinische Hochschule Hannover (DE)
- Clinical Innovations (United States) (US)
- Dana-Farber Cancer Institute (US)
- Syngene International (India) (IN)
- Synta Pharmaceuticals (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-05-09
- DOI
- https://doi.org/10.1038/s41467-026-72685-1
- Primary Topic
- Neuroendocrine Tumor Research Advances
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Damon Runyon Cancer Research Foundation
- V Foundation for Cancer Research
- St. Jude Children's Research Hospital
- Deutsche Forschungsgemeinschaft
- Else Kröner-Fresenius-Stiftung
- National Institutes of Health
- National Cancer Institute