c-Abl Modulates Tumor Cell Sensitivity to Antibody-Dependent Cellular Cytotoxicity

摘要: Monoclonal antibodies (mAb) can modulate cancer cell signal transduction and recruit antitumor immune effector mechanisms—including antibody-dependent cellular cytotoxicity (ADCC). Although several clinically effective promote ADCC, therapeutic resistance is common. We hypothesized that oncogenic signaling networks within tumor cells affect their sensitivity to ADCC. developed a screening platform targeted 60 genes derived from an EGFR gene network using RNAi in vitro ADCC model system. Knockdown of GRB7, PRKCE, ABL1 enhanced by primary secondary screens. knockdown also reduced proliferation, independent its enhancement effects. c-Abl overexpression decreased rescued the effects knockdown. Imatinib inhibition kinase activity ADCC—phenocopying knockdown—against EGFR-expressing head-and-neck squamous carcinoma lines ex vivo natural killer cells. Our findings suggest combining with ADCC-promoting antibodies, such as cetuximab, could translate into increased efficacy mAbs. Cancer Immunol Res; 2(12); 1186–98. ©2014 AACR.