|
|||||
|
|
Combinations of EGFR and MET inhibitors reduce proliferation and invasiveness of mucosal melanoma cells |
|
| Authors: | Aleksandra Simiczyjew Justyna Wądzyńska Magdalena Kot Marcin Ziętek Rafał Matkowski Mai P. Hoang Piotr Donizy Dorota Nowak |
| Affiliation: | 1. Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland;2. Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland Contribution: Formal analysis (equal), Investigation (equal), Methodology (equal), Writing - review & editing (equal);3. Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland Contribution: Investigation (equal), Methodology (equal), Writing - review & editing (equal);4. Department of Oncology and Division of Surgical Oncology, Wroclaw Medical University, Wroclaw, Poland Lower Silesian Oncology, Pulmonology and Hematology Center, Wroclaw, Poland Contribution: Methodology (equal), Writing - review & editing (equal);5. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA Contribution: Conceptualization (supporting), Writing - review & editing (equal);6. Department of Clinical and Experimental Pathology, Wroclaw Medical University, Wroclaw, Poland Department of Pathology and Clinical Cytology, Jan Mikulicz-Radecki University Hospital, Wroclaw, Poland Contribution: Conceptualization (equal), Funding acquisition (equal), Supervision (supporting), Writing - review & editing (equal) |
| Abstract: | Mucosal melanoma (MM) is a very rare and aggressive type of cancer for which immunotherapy or targeted therapy such as BRAF/MEK inhibitors, used in cutaneous melanoma, usually fail. Due to our earlier experience showing the high effectiveness of epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (MET) inhibitors in reducing the activation of the MAPK and PI3K/AKT signalling pathways, we aim to test whether these drugs would also be effective for mucosal melanoma. Cells representing two commercially available mucosal melanoma cell lines (GAK and HMVII) and one cell line obtained from a patient's vaginal melanoma were treated with MET or EGFR inhibitors, or combinations of these agents. The dual-inhibitor treatment strategy resulted in a decrease of cell proliferation, migration and invasion. Moreover, combinations of inhibitors led to reduction of pEGFR/EGFR and pMET/MET ratio and downregulation of PI3K/AKT and MEK/ERK1/2-based signalling pathways. Our findings indicate a potential therapeutic strategy based on EGFR and MET inhibitors in mucosal melanoma, which should be further evaluated in vivo and in clinical experiments. They also suggest that targeting multiple receptor tyrosine kinases may block signalling crosstalk and possibly delay the appearance of resistance to kinase inhibitors in mucosal melanoma cells. |
| Keywords: | crizotinib EGFR foretinib lapatinib MET mucosal melanoma signalling pathways |