Fenotipado de las mutaciones NRAS en cáncer colorrectal: caracterización clínico-molecular y búsqueda de nuevas terapias

ENG- Metastatic colorectal cancer (mCRC) remains a major medical challenge, particularly in the search for effective treatments such as epidermal growth factor receptor (EGFR)-targeted therapies. While mutations in the KRAS gene, present in 30-40% of patients, are widely recognized predictors of resistance to these therapies, the role of mutations in the NRAS gene, present in only 3-5% of cases, remains a mystery. To address this uncertainty, we conducted a study that combines both laboratory research and real-world clinical data. First, we used advanced gene-editing techniques known as CRISPR "gene scissors" to create cell models with specific mutations in the NRAS gene. This allowed us to study in detail how these mutations allow mCRC cells to escape the therapeutic effects of cetuximab. We identified two novel molecular mechanisms that contribute to cetuximab resistance in NRAS-mutant cells. These mechanisms involve hyperactivation of the MEK/ERK pathway and alteration of the signaling axis of the “ephrins" and their Eph receptors. Based on these findings, we evaluated new treatment combinations in preclinical cell models. We were able to demonstrate that the combination of cetuximab with MEK1/2 inhibitors produces a synergistic anti-tumor response, drastically augmenting the low efficacy of either treatment alone. In addition, the use of a "recombinant" version of a protein called ephrin-A1 is able to restore the sensitivity of NRAS-mutant cells to cetuximab. Our study also analyzed clinical data from more than 200 patients with mCRC in the province of Girona, providing invaluable insight into how different treatments affect patients in real-world practice. Our findings highlight the importance of taking NRAS genotype into account when designing mCRC treatment strategies. By integrating basic research with real-world clinical data, the results of our study open new possibilities for a more personalized and effective treatment of mCRC patients