Abstract 1084: Targeting MET and RON to overcome cetuximab resistance in colorectal cancer

Using a novel 3D culture system, we previously showed that activation of receptor tyrosine kinases (RTKs) MET and RON contributed to cetuximab resistance in colorectal cancer (CRC) cells. CC derived from HCA-7 cells were sensitive to cetuximab, whereas similarly derived SC were resistant; we also generated cetuximab-resistant (CC-CR) upon prolonged exposure of CC to cetuximab. 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. Moreover, MET and RON ligands, HGF and HGFL, respectively are synthesized as inactive precursors and require cleavage by proteases (HGFA, Matriptase, and Hepsin) to be biologically active. Herein, to inhibit HGF/HGFL cleavage in cetuximab-resistant cells, we employed inhibitors of proteases of HGF/HGFL (ZFH7116 and VD2173) and were able to overcome both de novo and acquired cetuximab resistance. We are now in the process of engineering cetuximab-sensitive CC cells to overexpress HGF or HGFL to test if ligand overexpression imparts cetuximab resistance and if this resistance can be overcome by inhibition of HGF/HGFL proteases and/or by crizotinib. To understand the broader significance of these resistance mechanisms, we have identified a set of KRAS wild-type human CRC patient-derived tumor xenografts (PDXs) that show increased MET/RON phosphorylation. A comparative RNA-seq analysis showed that PDXs with high pMET/pRON levels could be segregated from PDXs with low pMET/pRON levels. Differential response of these PDXs and their organoid (PDO) derivatives for cetuximab resistance and response to crizotinib addition based on their pMET/pRON levels will be presented. Citation Format: Ramona Graves-Deal, Galina Bogatcheva, Vishnu Damalanka, Lidija Klampfer, James W. Janetka, Robert J. Coffey, Bhuminder Singh. Targeting MET and RON to overcome cetuximab resistance in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1084.