ConcomitantBRAFandPI3K/mTORBlockadeIsRequiredfor Effective Treatment of BRAF V600E Colorectal Cancer

Purpose: BRAF V600E mutations are associated with poor clinical prognosis in colorectal cancer (CRC). AlthoughselectiveBRAFinhibitorsareeffectivefortreatmentofmelanoma,comparableeffortsinCRChave been disappointing. Here, we investigated potential mechanisms underlying this resistance to BRAF inhibitors in BRAF V600E CRC. Experimental Design: We examined phosphoinositide 3-kinase (PI3K)/mTOR signaling in BRAF V600E CRC cell lines after BRAF inhibition and cell viability and apoptosis after combined BRAF and PI3K/mTOR inhibition. We assessed the efficacy of in vivo combination treatment using a novel genetically engineered mouse model (GEMM) for BRAF V600E CRC. Results: Western blot analysis revealed sustained PI3K/mTOR signaling upon BRAF inhibition. Our BRAF V600E GEMM presented with sessile serrated adenomas/polyps, as seen in humans. Combination treatment in vivo resulted in induction of apoptosis and tumor regression. Conclusions: We have established a novel GEMM to interrogate BRAF V600E CRC biology and identify more efficacious treatment strategies. Combination BRAF and PI3K/mTOR inhibitor treatment should be explored in clinical trials. Clin Cancer Res; 19(10); 2688–98. � 2013 AACR.