A mechanism of BRAF inhibitor resistance of malignant melanoma by a novel regulatory mechanism of integrin-mediated survival signaling

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K07349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Yoneda Atsuko 東京薬科大学, 生命科学部, 講師 (80590372)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 糖鎖 / 脂質 / 悪性黒色腫 / 薬剤耐性

Outline of Final Research Achievements

Most malignant melanoma cases carry BRAF-active mutations, therefore the BRAF inhibitor is effective in treatments. But drug resistance eventually develops. This study examined whether changes in the integrin-survival signaling affected by alterations in cell surface glycosylation and in phospholipids in outer leaflet of plasma membranes involve in the BRAF inhibitor resistance of melanoma cells. Our results showed that CD63, an integrin signaling-associated molecule, was highly modified with polylactosamine sugar chains upon the BRAF inhibitor treatments, resulting in upregulated expression of cell surface CD63 and increases in the BRAF inhibitor susceptibility. We detected appearance of lipids, which are primarily located in inner leaflet of plasma membrane, in outer leaflet of melanoma cells, and exhibited its involvement in cell adhesion. These results may lead to develop a novel tool to treat drug-resistant malignant melanoma.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

がん化に伴って細胞表面の糖鎖構造が変化することは知られていたが、抗がん剤耐性に伴う変化については不明な点が多く、特に悪性黒色腫では報告がなかった。本研究では、抗がん剤処理により特定の糖鎖合成能が増加し、その結果CD63が細胞表面に多く出現することで薬剤に対する感受性が上がることを示した。また、細胞膜内膜にのみ存在するとされてきた特定のリン脂質が外膜にも出現することを検出し、この脂質が細胞接着に関わることを示唆した。これらの成果は、薬剤耐性悪性黒色腫の診断や治療法開発の基礎となろう。