Moshe Elkabets
Ben-Gurion University of the Negev, Israel
Title: MET activation drives resistance to cetuximab in head and neck cancer
Biography
Biography: Moshe Elkabets
Abstract
Background: Innate and acquisition of resistance to cetuximab, an epithelial growth factor receptor (EGFR) blocker, is major problem in metastatic head and neck squamous cell carcinoma (HNSCC). Although cetuximab significantly prolongs the median overall survival in HNSCC patients, only 15% of the patients experience a partial response, which lasts only several months.
Objectives: Investigate the role of c-MET expression and localization in response to cetuximab, and elucidate the signaling pathway downstream of c-MET that is responsible for tumor cells survival and proliferation.
Methods: Genomic, transcriptomics, and proteomics profiling was done on cetuximab-sensitive (CetuxSen) and resistant tumor (CetuxRes) lesions obtained from a patient who had an exceptionally good response to cetuximab monotherapy. Immunohistochemisty, FISH, and qPCR were applied to confirm MET localization, copy number, and expression, respectively. IHC staining and analysis of MET expression were done on 20-cetuximab treated patients. Biochemical studies in vitro were conducted to uncover the molecular mechanism of resistance.
Results: MET amplification and overexpression was observed in the CetuxRes tumor compared to the CetuxSen tumor. This was accompanied by a change in localization of MET. In the CetuxSen tumor MET was expressed mainly on the cell membrane, while in the CetuxRes MET was observed in the cytoplasm, indicating for its activity. In vitro studies verified that HGF/MET pathway activation is sufficient for conferring resistance to cetuximab mainly though reactivation of the MAPK pathway.
Conclusions: We show the first clinical evidence for MET-induced resistance to cetuximab in HNSCC. Evaluation of MET expression and localization may further improve decision making when treating with cetuximab.