Abstract 7046: BRAF/EGFR inhibition induces ERBB2 as a targetable tolerance mechanism in BRAF -mutant colorectal cancer.

Abstract Acquired drug resistance remains a major limitation to the long-term efficacy of targeted cancer therapies. The development of acquired resistance can involve the emergence of drug-tolerant persister (DTP) cells, which survive treatment through nongenetic adaptations such as activation of compensatory signaling pathways. Notably, Neuregulin 1 (NRG1) is a growth factor known to promote resistance to targeted therapies across multiple cancer types. This ligand engages the receptor tyrosine kinases ERBB3 and ERBB4, which bind it directly and signal through dimerization with ERBB2. This study aims to define the functional role of NRG1/ERBB signaling in DTPs arising from targeted inhibition of their oncogenic drivers and to evaluate strategies to inhibit this pathway to prevent acquired drug resistance. NRG1/ERBB pathway activity following targeted therapy was evaluated in a panel of oncogene-addicted cancer cell lines. CRISPR-Cas9-mediated ERBB knockouts were employed to assess the dependency of DTPs on these receptors. The efficacy of NRG1/ERBB axis inhibition with pan-ERBB inhibitors or ERBB-targeting antibody-drug conjugates was evaluated by Incucyte live-cell imaging and colony formation assays. Upregulation of the NRG1/ERBB signaling axis on transcriptional and protein level was observed in most tested oncogene-addicted cell lines upon therapy against their driver oncogene. Marked upregulation of ERBB2 was detected in drug-tolerant BRAF-mutant colorectal cancer (CRC) cell lines treated with dabrafenib and cetuximab. Our flow cytometry data suggest a shift from EGFR to ERBB2/ERBB3 signaling upon treatment in this cancer context. Furthermore, preliminary results using ERBB2 knockout cells demonstrate a dependency of ERBB2 in BRAF-mutant CRC DTPs under BRAF/EGFR inhibition. Combination of dabrafenib with a pan-ERBB inhibitor resulted in an improved treatment response in vitro compared to dabrafenib with cetuximab. Taken together, our data imply that drug tolerant BRAF-mutant CRC cells upregulate ERBB2/ERBB3 to resist BRAF/EGFR inhibition. Targeting the NRG1/ERBB signaling axis with a pan-ERBB inhibitor in combination with dabrafenib offers a potential strategy to prevent the emergence of resistance. Citation Format: Sara Peltola, Kari J. Kurppa, Klaus Elenius. BRAF/EGFR inhibition induces ERBB2 as a targetable tolerance mechanism in BRAF-mutant colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7046.