Abstract B021: Genome-wide CRISPR Screen Identifies Menin as a Mediator of Encorafenib Plus Cetuximab Resistance in BRAF V600E-mutant Colorectal Cancer

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Abstract Colorectal cancer (CRC) is the second most commonly diagnosed cancer and one of the leading causes of cancer-related deaths globally. Activating mutations in BRAF (V600E) occur in 5-10% of patients with metastatic CRC, and these patients have a significantly poorer prognosis. BRAF acts downstream of RAS in the MAPK signaling pathway, which drives cell proliferation, and aberrant activation of this pathway, through mutations in RAS or BRAF drives tumor development. Combination treatment with the mutant BRAF inhibitor Encorafenib, plus the EGFR inhibitor Cetuximab (EC) has significantly improved the overall survival of patients harboring BRAF V600E mutations, establishing it as the new standard of care for these patients. However, this treatment is not curative and both primary and secondary resistance remains a major clinical challenge. Understanding the molecular determinants of resistance to EC in BRAF V600E-mutant CRC is therefore critical for improving treatment strategies. To identify genetic drivers of resistance to EC, we performed whole-genome CRISPR screen in BRAF V600E-mutant CRC cells. Among candidate hits, MEN1 (Menin) emerged as a top driver of resistance. Functional validation using targeted CRISPR sgRNA-mediated knockout of MEN1 confirmed that loss of MEN1 significantly sensitizes BRAF V600E CRC cells to EC. Interestingly, this sensitization to EC was independent of the canonical Menin-MLL interaction, as neither pharmacological disruption of the Menin-MLL complex nor CRISPR-mediated knockout of MLL were able to recapitulate the sensitization to EC induced by MEN1-deletion. Detailed interrogation of the CRISPR screen data revealed consistent depletion of several c-Myc-target genes in the EC-treated condition. Since c-Myc is a well-known transcription factor downstream of the RAS-MAPK pathway, this observation suggested that c-Myc-driven transcriptional programs protect BRAF V600E tumors from EC treatment. Consistent with this hypothesis, EC treatment induced stronger suppression of c-Myc protein levels in MEN1-knockout cells, and RNA-seq analysis revealed enhanced downregulation of c-Myc-target genes in this context. Collectively, these results suggest that MEN1 sustains c-Myc-mediated transcription to confer resistance to EC. In summary, we identify Menin as a novel regulator of EC resistance in BRAF-mutant colorectal cancer, by modulating c-Myc-driven transcriptional programs. This study establishes a mechanistic link between a novel resistance node (MEN1) and MAPK-driven transcriptional regulation, highlighting the Menin/c-Myc axis as a promising therapeutic vulnerability. Targeting Menin in combination with Encorafenib plus Cetuximab may therefore provide a rational strategy to improve treatment outcomes for patients with BRAF V600E-mutant colorectal cancers. Citation Format: Akash Srivaths, Tirta M. Djajawi, Aleen Al Halawani, Kristen Needham, Chloe Gerak, Liam Neil, Sarahi Mendoza Rivera, Biswadeep Sen, Stephin J. Vervoort, John M. Mariadason, Conor J. Kearney. Genome-wide CRISPR Screen Identifies Menin as a Mediator of Encorafenib Plus Cetuximab Resistance in BRAF V600E-mutant Colorectal Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr B021.

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