Feasibility Of Combining Egfr- And Vegf(R)-Targeted Agents In Colorectal Cancer

443 Background: The extensive cross-talk between EGFR and VEGF(R) argues for joint targeting of the two signaling pathways. Unexpectedly, large clinical trials with combinations of EGFR-targeted antibodies and bevacizumab, a VEGF-blocking antibody, showed no added benefit in colorectal cancer (CRC) patients compared to bevacizumab alone. One difference between the antibodies and the small molecule tyrosine kinase inhibitors (TKIs) is the potential of the TKIs to inhibit intracellular signaling pathways. Methods: We here characterize the activity of two TKIs, the irreversible EGFR/HER2 inhibitor BIBW2992 (B2) and the VEGFR/PDGFR/FGFR inhibitor BIBF1120 (B1) toward human CRC models in vitro and in vivo. Results: B1 and B2 together showed strong activity toward HT-29 CRC xenografts, compared to either drug alone, and was associated with increased tumor cell death. In comparison, cetuximab and bevacizumab together were no more active than either drug alone and showed exclusively cytostatic activity. Recent findings provide evidence for intracellular VEGF-signaling in epithelial tumors which synergizes with EGFR for proliferation and survival (Cell 140:268, 2010). In agreement, HT-29 tumors expressed abundant intracellular VEGFR1 as shown by immunohistochemistry. Furthermore, targeted knock-down of VEGFR1 in cellular models was accompanied by increased sensitivity to B1 and B2 combinations thereby confirming the relevance of intracellular VEGFR1 signaling for CRC survival. Conclusions: Combinations of B1 and B2 show synergistic activity in CRC models. These findings favor clinical studies with combinations of the two agents and suggest that rationally selected EGFR- and VEGF-targeted agents can be combined for clinical benefit. [Table: see text]