Combinations of Bevacizumab and Erlotinib show activity in colorectal cancer independent of RAS status

Purpose: There is extensive cross-talk between VEGF- and EGFRpathway signaling in colorectal cancer (CRC). However, combinations of VEGF- and EGFR-targeted monoclonal antibodies (mAbs) show disappointing activity, in particular for patients with mutant RAS. Previous results show that tyrosine kinase inhibitors (TKIs) can be active in CRC models resistant to mAbs. This promoted us to examine whether the activity of bevacizumab can be increased by combination with erlotinib. Experimental design: The antitumor activity of bevacizumab, erlotinib and their combination was determined in CRC models with different RAS status and bevacizumab sensitivity. EGFR/VEGF pathway activation was characterized by immunohistochemistry, Western blot and ELISA assays. The influence of cetuximab and erlotinib on EGFmediated migration and the EGFR-EGF ligand feed-back loop was established in CRC cell lines with different RAS status. Results: The addition of erlotinib increased bevacizumab activity in all models independent of RAS status. Bevacizumab exposure was accompanied by marked EGFR activation in tumor cells as well as in tumor-associated endothelial cells (TECs) and resulted in strong accumulation of intracellular EGFR, which could be attenuated by erlotinib. In cellular models, erlotinib was able to attenuate EGFmediated functions in all cell lines independent of RAS status while cetuximab only showed activity in RAS wt cells. Conclusions: These results should provide a molecular framework to better understand the increased activity of the bevacizumab-erlotinib combination, compared to bevacizumab alone, in the GERCOR DREAM phase III clinical trial. Differential activity of mAbs and TKIs targeting the same signaling pathway is likely applicable for other tumor types.

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