| Autor: |
Elena, Elez, Javier, Ros, Jose, Fernández, Guillermo, Villacampa, Ana Belén, Moreno-Cárdenas, Carlota, Arenillas, Kinga, Bernatowicz, Raquel, Comas, Shanshan, Li, David Philip, Kodack, Roberta, Fasani, Ariadna, Garcia, Javier, Gonzalo-Ruiz, Alejandro, Piris-Gimenez, Paolo, Nuciforo, Grainne, Kerr, Rossana, Intini, Aldo, Montagna, Marco Maria, Germani, Giovanni, Randon, Ana, Vivancos, Ron, Smits, Diana, Graus, Raquel, Perez-Lopez, Chiara, Cremolini, Sara, Lonardi, Filippo, Pietrantonio, Rodrigo, Dienstmann, Josep, Tabernero, Rodrigo A, Toledo |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Nature medicine. 28(10) |
| ISSN: |
1546-170X |
| Popis: |
Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFsupV600E/supcolorectal cancer (mCRCsupBRAF-V600E/sup). 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 mCRCsupBRAF-V600E/suptreated 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-RNF43supmutated/supversus MSS-RNF43supwild-type/suptumors. 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-mCRCsupBRAF-V600E/suptumors 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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink