Discovery of molecular determinants of response to targeted therapies in colorectal cancer using patient-derived xenografts (‘xenopatients’)

Results Xenopatients retained the histological and genomic features of the original counterparts, responded to the anti-EGFR antibody cetuximab similarly to clinical observations, and could be prospectively stratified as responders or nonresponders based on predictive biomarkers. Genotype-response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/ NRAS/BRAF/PIK3CA wild-type cases. In this subset, combined HER2/EGFR inhibition induced long-lasting tumor regression. We also assessed the effects of MEK and PI3K/ mTor inhibitors (AZD6244 and BEZ235 respectively) in 40 specimens harboring KRAS/ NRAS/BRAF/PIK3CA mutations. Cotreatment of xenografts with AZD6244 +BEZ235 induced disease stabilization in the majority of cases (70%) but did not lead to tumor regression. Monotherapy was less effective, with BEZ235 displaying higher activity than AZD6244. Triple therapy with cetuximab provided further advantage. The extent of disease control declined upon prolonged treatment.