Antitumor effects of dabrafenib, trametinib, and panitumumab as single agents and in combination in BRAF-mutant colorectal carcinoma (CRC) models.

3513 Background: In contrast to BRAF-mutant melanoma, the inhibition of BRAF or BRAF/MEK has been relatively ineffective in the treatment of BRAF-mutant CRC, possibly due to EGFR-dependent resistance mechanisms. This study aimed to determine the anti-tumor activities for BRAF/MEK inhibition with or without EGFR inhibition in BRAFV600E CRC models and to identify biomarkers of response/resistance. Methods: We assessed cell growth inhibition, apoptosis and cell signaling changes by inhibitors of BRAF (dabrafenib, D), MEK (trametinib, T), and EGFR (panitumumab, P, cetuximab, and erlotinib) dosed as monotherapies and in combination in five BRAFV600E human CRC lines (Colo205, HT29, RKO, SW1417 and LS411N). Further, these inhibitors were evaluated for their anti-tumor effects either alone or in combination in two BRAFV600E CRC patient derived tumor xenografts (PDXs) established in female nude mice. One patient-derived xenograft (PDX) harbored the PIK3CAH1047R mutation (Co-018) and the other (Co-012) was wildtype...