EGFR和MET抑制剂的联合应用可降低黏膜黑素瘤细胞的增殖和侵袭性。
Combinations of EGFR and MET inhibitors reduce proliferation and invasiveness of mucosal melanoma cells.
发表日期：2023 Sep 07
作者：
Aleksandra Simiczyjew, Justyna Wądzyńska, Magdalena Kot, Marcin Ziętek, Rafał Matkowski, Mai P Hoang, Piotr Donizy, Dorota Nowak
来源：
Experimental Hematology & Oncology
摘要：
粘膜黑色素瘤（MM）是一种非常罕见且具侵袭性的癌症类型，免疫疗法或靶向治疗，如BRAF/MEK抑制剂，在表皮黑色素瘤中通常无效。由于我们早期的经验表明，表皮生长因子受体（EGFR）和肝细胞生长因子受体（MET）抑制剂在减少MAPK和PI3K/AKT信号通路激活方面具有很高的效果，因此我们旨在测试这些药物是否也对粘膜黑色素瘤有效。用代表两种商业可得的粘膜黑色素瘤细胞系（GAK 和 HMVII）和一种来自患者阴道黑色素瘤的细胞系，分别用MET或EGFR抑制剂，或两者的组合进行处理。双抑制剂治疗策略导致细胞增殖、迁移和浸润减少。此外，抑制剂的组合导致pEGFR/EGFR 和 pMET/MET比例降低，PI3K/AKT 和 MEK/ERK1/2信号通路下调。我们的研究结果表明在粘膜黑色素瘤中EGFR和MET抑制剂可能是一种潜在的治疗策略，需要在体内和临床实验中进一步评估。它们还表明，靶向多个受体酪氨酸激酶可能会阻断信号通讯，并可能延迟粘膜黑色素瘤细胞对激酶抑制剂的耐药性的出现。
© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
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.© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.