Abstract：
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.
摘要：
恶性黑色素瘤,侵袭性皮肤癌预后差,通常特征是BRAFV600E突变导致MAPK通路的激活以及黑素细胞的增殖和存活。BRAFV600E抑制剂，如vemurafenib和dabrafenib提高了患者的生存率，然而，耐药性仍然是一个重大挑战。我们研究了ERK5途径在BRAFV600E黑色素瘤细胞和对PLX4720（vemurafenib）和dabrafenib具有获得性抗性的细胞中的作用。在BRAFV600E黑色素瘤中，与ERK1/2抑制相比,ERK5抑制最低限度地影响生存力。在维罗非尼耐药细胞中，单独抑制ERK5不会影响生存力或恢复对维罗非尼的药物敏感性。然而,在dabrafenib抗性细胞中，ERK5抑制降低了活力并增强了MEK1/2抑制的抗增殖作用。靶向ERK5途径可能代表达拉非尼耐药黑色素瘤的治疗机会。
