Biologic Response of Colorectal Cancer Xenograft Tumors to Sequential Treatment with Panitumumab and Bevacizumab

Abstract Recent studies in RAS wild-type (WT) metastatic colorectal cancer (mCRC) suggest that the survival benefits of therapy using anti-epidermal growth factor receptor (anti-EGFR) and anti-vascular endothelial growth factor (anti-VEGF) antibodies combined with chemotherapy are maximized when the anti-EGFR antibody is given as first-line, followed by subsequent anti-VEGF antibody therapy. We report reverse- translational researchusing LIM1215 xenografts of RAS WT mCRC to elucidate the biologic mechanisms underlying this clinical observation. Sequential administration of panitumumabthen bevacizumab(PB) demonstrated a stronger tendency to inhibit tumor growth than bevacizumabthen panitumumab(BP). Cell proliferation was reduced significantly with PB ( P FASN, MVD) and hypoxia-related ( CA9, TGFBI) genes versus control. These results suggest that numerous mechanisms at the levels of gene expression, protein expression, and protein phosphorylationmay explain the improved clinical activity of PB over BP in patients with RAS WT mCRC.