Abstract 3451: Non-genetic RTK-mediated cetuximab resistance in colorectal cancer offers multiple targets for therapeutic intervention

Abstract

Abstract Using 3D type I collagen cultures of human colorectal cancer (CRC) cell line HCA-7 derivatives (CC, SC, CC-CR), we previously identified that activation of receptor tyrosine kinases (RTKs) MET and RON contributed to resistance to anti-EGFR monoclonal antibody, cetuximab. CC cells are sensitive to cetuximab, while SC and CC-CR cells are resistant in 3D. Both de novo and acquired modes of cetuximab resistance in SC and CC-CR, respectively, could be overcome by crizotinib, a multi-RTK inhibitor that also targets MET and RON. In fact, we now show that the cetuximab/crizotinib combination leads to synergistic growth inhibition in both SC and CC-CR. In addition to steady-state upregulation of MET and RON phosphorylation in SC cells, we also observe upregulation of ERBB3 phosphorylation after cetuximab addition, indicating a need for monitoring RTK activity during treatment. We have also identified a set of KRAS wild-type human CRC patient-derived tumor xenografts (PDXs) that show increased MET/RON phosphorylation. As noted previously, addition of the MET ligand (HGF) and ERBB3 ligand (NRG1) induced cetuximab resistance in CC cells and HGF-induced cetuximab resistance was overcome by crizotinib addition. We now show that MET/RON-dependent cetuximab resistance is due to autocrine production of their cognate ligands HGF/HGFL, respectively. For these studies, we employed selective inhibitors of the proteases (HGFA, Matriptase, and Hepsin) that mediate processing and maturation of HGF/HGFL; these inhibitors (ZFH7116 and VD2173) were able to overcome cetuximab resistance in SC and CC-CR cells. Thus, RTK ligand processing is an additional therapeutic target to counter cetuximab resistance in CRC. Citation Format: Ramona Graves-Deal, Galina Bogatcheva, Vishnu Damalanka, Lidija Klampfer, James W. Janetka, Robert J. Coffey, Bhuminder Singh. Non-genetic RTK-mediated cetuximab resistance in colorectal cancer offers multiple targets for therapeutic intervention [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3451.