恶性黑色素瘤是一种预后不良的侵袭性皮肤癌，其特征通常是 BRAFV600E 突变，导致 MAPK 通路激活以及黑色素细胞增殖和存活。维莫非尼和达拉非尼等 BRAFV600E 抑制剂提高了患者的生存率，但耐药性仍然是一个重大挑战。我们研究了 ERK5 通路在 BRAFV600E 黑色素瘤细胞以及对 PLX4720（vemurafenib）和 dabrafenib 获得性耐药的细胞中的作用。在 BRAFV600E 黑色素瘤中，与 ERK1/2 抑制相比，ERK5 抑制对活力的影响最小。在威罗非尼耐药细胞中，单独抑制 ERK5 不会影响细胞活力或恢复对威罗非尼的药物敏感性。然而，在达拉非尼耐药细胞中，ERK5 抑制会降低活力并增强 MEK1/2 抑制的抗增殖作用。靶向 ERK5 通路可能代表达拉非尼耐药黑色素瘤的治疗机会。© 2024 作者。约翰·威利 (John Wiley) 出版的 FEBS 快报

Malignant melanoma, an aggressive skin cancer with a poor prognosis, frequently features BRAFV600E mutation resulting in activation of the MAPK pathway and melanocyte proliferation and survival. BRAFV600E inhibitors like vemurafenib and dabrafenib have enhanced patient survival, yet drug resistance remains a significant challenge. We investigated the role of the ERK5 pathway in BRAFV600E melanoma cells and cells with acquired resistance to PLX4720 (vemurafenib) and dabrafenib. In BRAFV600E melanoma, ERK5 inhibition minimally affected viability compared to ERK1/2 inhibition. In vemurafenib-resistant cells, ERK5 inhibition alone didn't impact viability or restore drug sensitivity to vemurafenib. However, in dabrafenib-resistant cells, ERK5 inhibition reduced viability and enhanced the anti-proliferative effect of MEK1/2 inhibition. Targeting the ERK5 pathway may represent a therapeutic opportunity in dabrafenib-resistant melanoma.© 2024 The Author(s). FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.