BRAF V600E confers resistance to cetuximab or panitumumab metastatic colorectal cancer

Background: Cetuximab and panitumumab are effective in only 10−20% of patients with metastatic colorectal cancer (mCRC). The occurrence of KRAS mutations accounts for about 30−40% of the non-responsive cases. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in the absence of KRAS mutations, resistance to anti- EGFR treatments could be caused by alterations occurring in BRAF. Patients and Methods: We retrospectively analyzed the mutational status of KRAS in 114 tumors from cetuximab- or panitumumab-treated mCRC patients. Mutational analysis of BRAF exon 15 was carried out in samples that were wild type for KRAS. We further studied the effect of the BRAF V600E mutation on response to cetuximab and panitumumab using in vitro models of mCRC. Results: KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = 0.006). The BRAF V600E mutation was detected in 11 patients out of 80 who had wild type KRAS. None of the BRAF mutated patients responded to treatment, while none of the responders carried BRAF mutations (P = 0.028). Patients with BRAF mutated tumors had significantly shorter progression-free and overall survival than wild-type cases. In cellular models of CRCs, introduction of the oncogenic BRAF V600E allele dramatically impaired the therapeutic effect of cetuximab and panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to anti EGFR antibodies of colorectal cancer cells carrying the V600E allele. The synergistic effect of cetuximab and sorafenib was associated with massive induction of caspase-mediated apoptosis in BRAF mutated cells. Conclusions: These results show that BRAF wild type is required for response to anti-EGFR monoclonal antibody and could be useful as a biomarker to select patients eligible for treatment. They also strongly support ‘double hit’ therapies aimed at simultaneous inhibition of EGFR and BRAF in colorectal cancers carrying oncogenic activation of BRAF.