Show Notes
Bourgeois et al., Nature Communications - This study used enhanced CRISPR base editor screens, structural biology, biochemical assays, and in vitro/in vivo selection to map MEN1 mutations that drive resistance to five clinical menin inhibitors and to explain their mechanisms. Key terms: MEN1, menin inhibitors, CRISPR base editing, drug resistance, KMT2A.
Study Highlights:
CRISPR base editor screens tiled MEN1 and profiled resistance to five clinical menin inhibitors, revealing shared (M327 I/V/T, G331D) and inhibitor-specific (C334R, E368K/V, V372A) substitutions. Co-crystal structures of mutant menin bound to each inhibitor explain resistance via steric clashes or disrupted interactions and correlate with measured Ki and cellular IC50 shifts. Orthogonal in vitro selection and PDX experiments show many predicted mutations arise spontaneously under drug pressure and that higher inhibitor potency or dosing can suppress or overcome some resistant clones. The particular amino acid substitution at a residue critically determines the magnitude and breadth of resistance.
Conclusion:
Enhanced CRISPR base editing combined with structural and biological validation maps a mutational landscape in MEN1 that can produce pan-class or drug-specific resistance to menin inhibitors; these data can guide clinical monitoring, choices between inhibitors, dosing strategies, and next-generation inhibitor design.
Music:
Enjoy the music based on this article at the end of the episode.
Article title:
CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials
First author:
Bourgeois
Journal:
Nature Communications
DOI:
10.1038/s41467-026-72685-1
Reference:
Bourgeois, W., Rice, H.E., Wenge, D.V. et al. CRISPR base editor screening identifies spectrum of MEN1 mutations impacting menin inhibitors in clinical trials. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72685-1
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
Support:
Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00
Official website https://basebybase.com
On PaperCast Base by Base you'll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
Episode link: https://basebybase.com/episodes/papercast-base-by-base-menin-mutations-365
QC:
This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-05-15.
QC Scope:
- article metadata and core scientific claims from the narration
- excludes analogies, intro/outro, and music
- transcript coverage: Audited the transcript sections describing the CRISPR base editor screen identifying MEN1 mutations that affect five clinical menin inhibitors, including shared vs inhibitor-specific mutations, biochemical and structural validation, and in vivo PDX confirmation, as well as dose-related resistance dynamics and limitatio
- transcript topics: Menin-KMT2A interaction and menin inhibitors in leukemia; CRISPR base editor screen design and MV4;11 cells; Shared and inhibitor-specific MEN1 mutations (M327, G331, T349, C334R, E368K/V, V372A); Biochemical binding: TR-FRET and Ki shifts; Structural insights: co-crystal structures; In vivo validation: PDX models
QC Summary:
- factual score: 10/10
- metadata score: 10/10
- supported core claims: 6
- claims flagged for review: 0
- metadata checks passed: 4
- metadata issues found: 0
Metadata Audited:
- article_doi
- article_title
- article_journal
- license
Factual Items Audited:
- Five inhibitors tested: DS-1594, JNJ-6617, KO-539, SNDX-5613, DSP-5336
- Base editing screen in MV4;11 A>G and C>T lines mutates MEN1 across residues; screen yields enriched residues near the KMT2A binding pocket
- Mutations show shared (pan-class) resistance, notably M327I and G331D, and inhibitor-specific resistance (C334R for DS-1594; E368K/V for DSP-5336; V372A for KO-539)
- Ki shifts measured by TR-FRET correlate with cellular IC50 shifts
- Co-crystal structures explain resistance via steric clashes or disrupted interactions
- In vivo PDX validation shows mutations arise under therapeutic pressure; higher potency can suppress or overcome resistance
QC result: Pass.
