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<p>Menin inhibitors have entered clinical trials for <i>histone lysine methyltransferase 2 A (KMT2A)</i>-rearranged and <i>nucleophosmin 1 (NPM1)</i>-mutant acute leukemias and are demonstrating promising activity. CRISPR base editor screening previously predicted several <i>MEN1</i> (menin) mutations that have arisen in patients receiving SNDX-5613 and confer resistance. The extent to which <i>MEN1</i> mutations will impact each menin inhibitor is mostly unknown. Here we show that CRISPR base editor screens can be leveraged to profile the <i>MEN1</i> 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 <i>MEN1</i> mutation generation under therapeutic pressure suggest the <i>MEN1</i> mutations identified with CRISPR base editor screening are likely to arise and impact all menin inhibitors.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月9日

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  • Wallace Bourgeois,
  • Hannah E. Rice,
  • Daniela V. Wenge,
  • Florian Perner,
  • Hong Yue,
  • Brandon D. Regalado,
  • George Wan,
  • Jan C. Schroeder,
  • Alba Sommerschield,
  • Charlie Hatton,
  • Shivendra Singh,
  • Sweta Singh,
  • Shipra Bijpuria,
  • Brian M. McKeever,
  • William H. Miller,
  • Jordan F. Safer,
  • Sumaiya Iqbal,
  • Jennifer A. Perry,
  • Eric S. Fischer,
  • John G. Doench,
  • Gerard M. McGeehan,
  • Jevon A. Cutler,
  • Scott A. Armstrong

摘要

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.