Monoclonal antibodies can modulate cancer cell signal transduction and recruit anti-tumor immune effector mechanisms - including antibody-dependent cellular cytotoxicity (ADCC). Although several clinically effective antibodies can promote ADCC, therapeutic resistance is common. We hypothesized that oncogenic signaling networks within tumor cells affect their sensitivity to ADCC. We developed a screening platform and targeted 60 genes derived from an EGFR gene network using RNA interference (RNAi) in an in vitro ADCC model system. Knockdown of GRB7, PRKCE, and ABL1 enhanced ADCC by primary and secondary screens. ABL1 knockdown also reduced cell proliferation, independent of its ADCC enhancement effects. c-Abl overexpression decreased ADCC sensitivity and rescued the effects of ABL1 knockdown. Imatinib inhibition of c-Abl kinase activity also enhanced ADCC - phenocopying ABL1 knockdown - across several EGFR-expressing head-and-neck squamous cell carcinoma (HNSCC) cell lines by ex vivo primary NK cells. Our findings suggest that combining c-Abl inhibition with ADCC-promoting antibodies, such as cetuximab, could translate into increased therapeutic efficacy of monoclonal antibodies.
- Received May 1, 2014.
- Revision received September 8, 2014.
- Accepted October 2, 2014.
- Copyright © 2014, American Association for Cancer Research.