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 for PIK3CA. Results: In three out of five lines, all three EGFR inhibitors enhanced cell growth inhibition by D and the combination of D/T. Adding P to D or to the combination of D/T led to sustained suppression of pERK. The triple combination of P/D/T most effectively inhibited both pERK and pS6, and increased PARP cleavage in HT29 cells. P significantly improved the efficacy of either D or D/T in the Co-012 and Co-018 models. The triple combination of P/D/T was highly efficacious in both PDXs, and more effectively delayed tumor growth than the combination of P/D or D/T in Co-018 model, while D and P alone showed little or no activity. Pharmacodynamic changes and baseline characterization including expression levels of EGFR and EGFR ligands are under evaluation, and will be tested in clinical samples. Conclusions: While inhibition of MAPK or EGFR signaling has limited activity in BRAF-mutant CRC, the combined inhibition of MAPK signaling and EGFR has significant anti-tumor activity, with the triple combination being the most efficacious in preclinical models of BRAFV600E CRC. The results support ongoing clinical trials of D/T/P combinations in subjects with V600E BRAF-mutation positive CRC.