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RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAF(V600E) metastatic colorectal cancer
Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAF(V600E) colorectal cancer (mCRC(BRAF-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 disco...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9556333/ https://www.ncbi.nlm.nih.gov/pubmed/36097219 http://dx.doi.org/10.1038/s41591-022-01976-z |
Sumario: | Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAF(V600E) colorectal cancer (mCRC(BRAF-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 mCRC(BRAF-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-RNF43(mutated) versus MSS-RNF43(wild-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-mCRC(BRAF-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. |
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