RNF43mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600Emetastatic colorectal cancer

Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600Ecolorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600Etreated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43mutations to predicting clinical benefit (72.7% versus 30.8%; P= 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P= 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P= 0.008), in patients with MSS-RNF43mutatedversus MSS-RNF43wild-typetumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600Etumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.