Abstract
Abstract Monoclonal antibodies can induce antibody-dependent cellular cytotoxicity (ADCC) through immune effector cells, such as natural killer (NK) cells. Although clinical evidence suggests a role for ADCC in effective antibody therapy of cancer, molecular determinants of ADCC responsiveness—in oncogenic signaling networks, for example—have not been well characterized. Using an in vitro model system including an NK-like cell line (NK92-CD16V), cetuximab, and A431 cells, we screened 60 genes from an EGFR gene network by RNAi to assess for synthetic enhancement of ADCC. Primary and validation screens, and correlative characterization studies, identified four genes whose knockdown enhanced ADCC: GRB7, PRKCE, RET, and ABL1. Inhibition of Abl kinase activity enhanced ADCC, phenocopying the effects of ABL1 knockdown and providing pre-clinical evidence for combining Abl inhibitors and cetuximab. Next, we derived an ADCC-resistant cell population (A431/ADCC-R) by treating parental A431 cells with over 30 successive ADCC treatments. We describe the development, screening, and characterization of A431/ADCC-R. Our screening strategy has revealed molecular determinants of both tumor cell sensitivity and resistance to ADCC in vitro that may translate into increased monoclonal antibody efficacy in the clinic. Citation Format: Joseph C. Murray, Rochelle E. Nasto, Sandra A. Jablonski, Yong Tang, Louis M. Weiner. Molecular determinants of sensitivity and resistance to tumor-directed antibody-dependent cellular cytotoxicity (ADCC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2847. doi:10.1158/1538-7445.AM2013-2847
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