Abstract 2389: Role of MET in head and neck cancer

Abstract

Abstract Introduction c-MET is a well-known target due to its amplification and overexpression in gastric cancer and NSCLC. Overexpression has also been reported for Head and Neck Cancer (HNSCC), but initial clinical trials with MET inhibitors in HNSCC have not been successful. Methods We investigated the expression level of MET in HNSCC and also characterized the molecular activity level based on the phosphorylation of the intracellular adaptor protein docking site, Tyrosine-1349. In a second larger cohort, we tested expression of MET and correlate it with follow-up data in order to test the prognostic relevance of MET expression in gastric cancer. All clinical samples were all obtained in compliance with clinical regulations and informed consent of every patient. Results We found MET clearly overexpressed in HNSCC. However, the signaling activity of MET was not elevated compared to normal adjacent tissue. To test the relevance of MET for growth of HNSCC cells, we tested the activity of BAY 853474 in a panel of HNSCC cell lines. In contrast to gastric cancer control cell lines which had low nanomolar IC50 values, none of the 12 HNSCC cell lines was sensitive to MET inhibition. This was in contrast to their sensitivity to Cisplatin/Fluoruracil as positive control. Compared to MET dependent cell lines from gastric cancer, HNSCC cell lines had 10 fold less MET expression. The phosphorylation was two orders of magnitude below that of responder cell lines. On the molecular level, we also compared the properties of the HNSCC cell lines with that of fresh frozen tumor biopsies from 50 patients. In this analysis, it became evident that clinical samples had strikingly lower MET expression and phosphorylation even compared to the HNSCC cell lines. Based on these findings, a clinical response to MET inhibitors cannot be expected. In a larger cohort of several hundred patients, we are currently testing whether the elevated MET expression may still be prognostic for progression and/or survival. It appears possible that MET expression may give a growth advantage to tumor cells although it is clearly not fulfilling the criteria for an oncogenic driver in this indication. The significant overexpression of MET in tumor tissue and the very strong overexpression in cell lines compared to clinical samples show that MET expression gives a selective advantage to the tumor cells. We will show whether this advantage results in shorter time to progression or overall survival. Conclusion We show that MET expression in HNSCC cell lines is not representative for the clinical situation. HNSCC does not overexpress Met and the molecular activity is low. MET is devalidated as therapeutic target in HNSCC. An analysis of the prognostic value of MET expression in HNSCC will follow and presented at the AACR meeting in 2018. Citation Format: Thomas Schlange, Martin Khan, Sami Khaznadar, arndt schmitz, Thomas Krahn, Oliver von Ahsen. Role of MET in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2389.