title: c-Abl modulates tumor cell sensitivity to antibody-dependent cellular cytotoxicity.
abstract: 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 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 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-against several EGFR-expressing head-and-neck squamous cell carcinoma cell lines by ex vivo primary natural killer cells. Our findings suggest that combining c-Abl inhibition with ADCC-promoting antibodies, such as cetuximab, could translate into increased therapeutic efficacy of mAbs.
authors.affiliation: Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Dalal
authors.initials: D
authors.lastname: Aldeghaither
authors.affiliation: Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Shangzi
authors.initials: S
authors.lastname: Wang
authors.affiliation: Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC. School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, Pennsylvania. Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Rochelle E
authors.initials: RE
authors.lastname: Nasto
authors.affiliation: Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Jablonski
authors.affiliation: Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC.
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Georgetown Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC. weinerl@georgetown.edu.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Weiner
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D058846:Antibodies, Monoclonal, Murine-Derived / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D023281:Genomics / Q000379:methods; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics*; D034622:RNA Interference; D015203:Reproducibility of Results; D000069283:Rituximab
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D000069283:Rituximab; D016315:Proto-Oncogene Proteins c-abl