Combinations of EGFR and MET inhibitors reduce proliferation and invasiveness of mucosal melanoma cells

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...

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Published in:Journal of cellular and molecular medicine 2023-10, Vol.27 (19), p.2995-3008
Main Authors: Simiczyjew, Aleksandra, Wądzyńska, Justyna, Kot, Magdalena, Ziętek, Marcin, Matkowski, Rafał, Hoang, Mai P., Donizy, Piotr, Nowak, Dorota
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Biotechnology
c-Met protein
Cell culture
Cell growth
Cell migration
Cell proliferation
Down-regulation
Epidermal growth factor
Epidermal growth factor receptors
Experiments
Extracellular signal-regulated kinase
Hepatocyte growth factor
Immunotherapy
Invasiveness
Kinases
MAP kinase
Medical prognosis
MEK inhibitors
Melanoma
Metastasis
Mucosa
Mutation
Original
Patients
Penicillin
Signal transduction
Vagina
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Summary: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.
ISSN:1582-1838
1582-4934
DOI:10.1111/jcmm.17935