Abstract 4156: Molecular and phenotypic characterization of breast and colorectal cancer cells selected for resistance to antibody-dependent cell-mediated cytotoxicity (ADCC)

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.4156-4156
• Main Authors: Biswas, Tanuka, Fritzemeier, Rebecca, Mark, Adam, Meißner, Tobias, Young, Brandon, Jones, Brian-Leyland, Pegram, Mark
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-4156

Monoclonal antibody (mAb) therapy is limited by clinical resistance. For example, alterations in PI3K/Akt /Ras-MAPK signaling, over activation/expression of alternate receptor kinases (c-Met/ IGF-1R), or proteolysis of extracellular domains harboring target epitopes are postulated mechanisms of clinical resistance to trastuzumab. ADCC is a major mechanism of action for mAbs. Most studies have focused on cell models of resistance through in vitro selection, in presence of mAbs, in the absence of immune effector cells. We developed a unique model of immune selection, where target cells (HER2 +ve breast cancer cells SKBR3, BT474; and EGFR +ve colon cancer cells HT29, DLD1) were subjected to ADCC (>90% cell death) with saturating concentrations of trastuzumab or cetuximab (100 µg/ml), respectively, and human peripheral blood mononuclear cells (PBMCs). Selection (in triplicate) was continued for 10 consecutive passages and surviving cells were allowed to grow to confluence over a period of 8-10 weeks. Mock-treated parent cells, IgG1 isotype control, mAb-alone and PBMCs only were utilized as controls. Compared to parent controls, immune-selected DLD1 and SKBR3 cells demonstrated statistically significant increase in proliferation (WST viability assays, P