Acquired Resistance in BRAF V600E-Mutant MSS Colorectal Cancer: Two Cases Highlighting Molecular Adaptation and Salvage Strategies

Abstract BRAF V600E mutations in metastatic colorectal cancer (mCRCs) are associated with aggressive tumor behavior and poor prognosis, with limited benefit from BRAF inhibitors due to rapid resistance mechanisms. Here, we report the two cases of microsatellite-stable, BRAF V600E-mutated mCRC demonstrating resistance to multiple lines of therapy, including BRAF/epidermal growth factor receptor inhibition. In both cases, comprehensive molecular profiling identified co-occurring mutations associated with immune escape and pathway reactivation. Rational off-label therapeutic combinations of regorafenib plus nivolumab in one patient and dabrafenib, trametinib and cetuximab in the other were associated with clinical benefit. These cases highlight the role of serial molecular reassessment and individualized treatment strategies for patients with BRAF V600E-mutant mCRC.