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Murray JC , Aldeghaither D , Wang S , Nasto RE , Jablonski SA , Tang Y , Weiner LM
c-Abl modulates tumor cell sensitivity to antibody-dependent cellular cytotoxicity
Cancer Immunol Res. 2014 Dec;2(12) :1186-98
PMID: 25300860 URL: http://www.ncbi.nlm.nih.gov/pubmed/25300860
AbstractMonoclonal 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.
NotesMurray, Joseph C Aldeghaither, Dalal Wang, Shangzi Nasto, Rochelle E Jablonski, Sandra A Tang, Yong Weiner, Louis M ENG P30-CA051008/CA/NCI NIH HHS/ R01 CA050633/CA/NCI NIH HHS/ P30 CA051008/CA/NCI NIH HHS/ T32 CA009686/CA/NCI NIH HHS/ F30 CA165474/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural 2014/10/11 06:00 Cancer Immunol Res. 2014 Dec;2(12):1186-98. doi: 10.1158/2326-6066.CIR-14-0083. Epub 2014 Oct 9.