Abstract 4604: Implications of genomic alterations in RNF43 and RSPO3 for the response of BRAFV600E metastatic colorectal cancer to anti-EGFR+BRAF combinatory therapy

Abstract The BRAFV600E mutation, present in 8 - 10% of colorectal cancers (CRCs), is associated with poor patient outcome and has limited treatment options. Recent studies have shown that mutations in the E3 ubiquitin ligase RNF43 predict response to anti-EGFR/BRAF combinatory therapy in patients with BRAFV600E metastatic CRC. Gene expression analysis of CRCs with the BRAF/RNF43 co-mutation exhibit significantly higher expression levels of MAP2K1 and MAPK3 compared to their wild-type counterparts. This implies an unknown but clinically significant molecular relationship between RNF43 loss-of-function and the MAPK signaling pathway. RNF43 attenuates WNT signaling by promoting the endocytosis and lysosomal degradation of Frizzled receptors to desensitize the cells to WNT ligands. RNF43 itself is in turn negatively regulated by the R-spondin (RSPO) family of proteins. Activating fusions involving RSPOs and inactivating mutations in RNF43 are found in ∼2% and ∼5% of CRCs, respectively. The aim of the present project is to better understand how gene alterations affecting the R-spondin/RNF43 signaling module influence the response to EGFR/BRAF inhibitor combination treatment. We use patient-derived organoids with different genomic alterations in BRAF and RNF43, APC, or RSPO3 as preclinical models to elucidate signaling dynamics before and after treatment with EGFR and BRAF inhibitors alone or in combination. This analysis includes various omics approaches such as mass spectrometry, RNA sequencing and kinome profiling. Here, we present preliminary results from this study, showing how these treatments differentially affect MAPK and WNT signaling depending on the mutational profile of the organoids Citation Format: Jakob M. Stenersen, Max Z. Totland, Luís Nunes, Ina A. Eilertsen, Vilde C. Elster, Tuula A. Nyman, Ragnihild A. Lothe, Anita Sveen, Kushtrim Kryeziu, Edward Leithe. Implications of genomic alterations in RNF43 and RSPO3 for the response of BRAFV600E metastatic colorectal cancer to anti-EGFR+BRAF combinatory therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4604.