2. Academic Validation
  3. CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials

CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials

  • Nat Commun. 2026 May 9. doi: 10.1038/s41467-026-72685-1.
Wallace Bourgeois 1,  Hannah E Rice 1,  Daniela V Wenge 1 2,  Florian Perner 2,  Hong Yue 3 4,  Brandon D Regalado 1,  George Wan 1,  Jan C Schroeder 1,  Alba Sommerschield 1,  Charlie Hatton 1,  Shivendra Singh 5,  Sweta Singh 5,  Shipra Bijpuria 5,  Brian M McKeever 6,  William H Miller 7,  Jordan F Safer 8,  Sumaiya Iqbal 8,  Jennifer A Perry 1,  Eric S Fischer 3 4,  John G Doench 9,  Gerard M McGeehan 10,  Jevon A Cutler 11 12,  Scott A Armstrong 13
Affiliations

Affiliations

  • 1 Department of Pediatric Oncology, Dana-Farber Cancer Institute; Division of Hematology/Oncology, Boston Children's Hospital; Harvard Medical School, Boston, MA, USA.
  • 2 Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School (MHH), Hannover, Germany.
  • 3 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 4 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA.
  • 5 Syngene International Limited, Bangalore, India.
  • 6 Brian M. McKeever, LLC, Lake Ronkonkoma, NY, USA.
  • 7 MedChem Innovations, LLC, Collegeville, PA, USA.
  • 8 Ladders To Cures Accelerator, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 9 Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 10 Syndax Pharmaceuticals, Inc, Waltham, MA, USA.
  • 11 Department of Pediatric Oncology, Dana-Farber Cancer Institute; Division of Hematology/Oncology, Boston Children's Hospital; Harvard Medical School, Boston, MA, USA. [email protected].
  • 12 Departments of Pediatrics and Cell, Developmental and Cancer Biology, Knight Cancer Institute, Oregon Health and Science University (OHSU), Portland, OR, USA. [email protected].
  • 13 Department of Pediatric Oncology, Dana-Farber Cancer Institute; Division of Hematology/Oncology, Boston Children's Hospital; Harvard Medical School, Boston, MA, USA. [email protected].
PMID: 42103719 DOI: 10.1038/s41467-026-72685-1
Abstract

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.

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