Acquired resistance to BRAF inhibitory treatments requires tumor tissue remodeling and reveals targetable vulnerabilities in colorectal cancer

<title>Abstract</title> The combination of BRAF^V600E and EGFR inhibitors benefits advanced colorectal cancer (CRC) patients, but resistance can develop through non-genetic mechanisms not fully understood. This study reveals that <italic>BRAF</italic> mutant CRC tumors undergo a tissue remodeling to resist BRAF^V600E inhibitors, characterized by tumor cell mucinous differentiation and extracellular matrix transformation, allowing an increased infiltration of activated fibroblasts, immune cells, and vasculature. Some of these changes are essential for acquiring resistance. In fact, we demonstrate that blocking new vascularization with the anti-angiogenic antibody bevacizumab against VEGFA extends the benefit of BRAF inhibitory therapies in CRC models. These findings are based on patient-derived xenograft (PDX) models and validated in patient samples, offering deeper insights into resistance mechanisms and suggesting rational combinations to prolong therapy effectiveness. A clinical trial is being initiated to test the combination of bevacizumab and BRAF inhibitory therapy for improving CRC patients’ treatment.