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RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Elez, Elena, Ros, Javi, Fernandez, Jose, Villacampa, Guillermo, Kodack, David, Moreno, Ana Belen, Arenillas, Carlota, Li, Shanshan, Dienstmann, Rodrigo, Bernatowicz, Kinga, Fasani, Roberta, Comas, Raquel, Garcia, Ariadna, Gonzalez-Ruiz, Javi, Piris-Gimenez, Alejandro, Nuciforo, Paolo, Perez-Lopez, Raquel, Vivancos, Ana, Smits, Ron, Randon, Giovanni, Graus-Porta, Diana, Cremolini, Chiara, Lonardi, Sara, Pietrantonio, Filippo, Tabernero, Josep, Toledo, Rodrigo, Kerr, Grainne, Montagna, Aldo, Germani, Marco Maria and Intini, Rossana (2022) RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer. Nature medicine, 28 (10). pp. 2162-2170. ISSN 1546-170X; 1078-8956


Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal 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-V600E treated 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 RNF43 mutations 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-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors 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.

Item Type: Article
Date Deposited: 29 Nov 2022 00:46
Last Modified: 29 Nov 2022 00:46


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