Melanoma is the most aggressive form of skin cancer. Together with the recent advances in immunotherapy, targeted therapy with inhibitors of the Mitogen Activated Protein Kinase (MAPKi) pathway including BRAF and MEK inhibitors has greatly improved the clinical outcome of these patients. Unfortunately, due to genetic and non-genetic events, many patients develop resistance to MAPKi. Melanoma phenotypic plasticity, understood as the ability of melanoma cells to dynamically transition between different states with varying levels of differentiation/dedifferentiation, is key for melanoma progression. Lineage plasticity has also emerged as an important mechanism of non-genetic adaptive melanoma drug resistance in the clinic (Arozarena & Wellbrock, 2019), highlighting the need for a deeper characterization of the mechanisms that control this process. In this issue of EMBO Molecular Medicine, Diazzi et al (2022) identify a mechanism regulating MAPKi-induced phenotypic plasticity and resistance, providing evidence to support the use of an anti-fibrotic drug as a potential novel combinatorial therapeutic approach.

中文翻译：

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抗纤维化药物作为耐药黑色素瘤的治疗工具

黑色素瘤是最具侵袭性的皮肤癌。连同免疫疗法的最新进展，包括 BRAF 和 MEK 抑制剂在内的丝裂原活化蛋白激酶 (MAPKi) 通路抑制剂的靶向治疗极大地改善了这些患者的临床结果。不幸的是，由于遗传和非遗传事件，许多患者对 MAPKi 产生耐药性。黑色素瘤表型可塑性，被理解为黑色素瘤细胞在具有不同分化/去分化水平的不同状态之间动态转换的能力，是黑色素瘤进展的关键。谱系可塑性也已成为临床上非遗传适应性黑色素瘤耐药性的重要机制（Arozarena & Wellbrock，2019），强调需要更深入地描述控制这一过程的机制。等人(2022) 确定了调节 MAPKi 诱导的表型可塑性和抗性的机制，为支持使用抗纤维化药物作为潜在的新型组合治疗方法提供了证据。