440 Background: Monoclonal antibodies against the epidermal growth factor receptor (EGFR) have improved treatment options for colorectal cancer (CRC), but tumors harboring RAS mutations are resistant. Full molecular understanding of RAS-mediated protection is key to the development of sensitization strategies. Methods: We have used cell culture and murine CRC transplant models to study whether RAS solely imposes resistance by compensating EGFR signaling blockade, or additionally interferes with antibody-dependent cellular cytotoxicity (ADCC). Results: Both clinically approved anti-EGFR antibodies, cetuximab and panitumumab, were equally cytotoxic in CRC cells in vitro. Interestingly, cetuximab, a chimeric IgG1 antibody capable of triggering ADCC, was more effective than panitumumab (human IgG2) in murine CRC transplant models in vivo. The advantage of cetuximab in vivo was completely abolished by leukocyte depletion following total body irradiation. Moreover, oncogenic RAS neutralized the in vivo therapeutic activity of cetuximab and panitumumab to the same extent. Mechanistically, RAS conferred antibody resistance by upregulation of BCL-XL, which was overcome by cotreatment with a BH3 mimetic. In support, RAS-mutant primary human CRCs exhibited increased BCL-XL expression as detected by immunohistochemistry. Conclusions: RAS-mutant CRCs escape anti-EGFR antibody-mediated receptor blockade as well as ADCC in vivo. Pharmacologic modulation of RAS downstream effectors, such as BCL-XL, can restore sensitivity to antibody effector mechanisms. [Table: see text]