Despite substantial clinical benefit of targeted and immune checkpoint blockade-based therapies in melanoma, resistance inevitably develops. We show cytoskeletal remodeling and changes in expression and activity of ROCK-myosin II pathway during acquisition of resistance to MAPK inhibitors. MAPK regulates myosin II activity, but after initial therapy response, drug-resistant clones restore myosin II activity to increase survival. High ROCK-myosin II activity correlates with aggressiveness, identifying targeted therapy- and immunotherapy-resistant melanomas. Survival of resistant cells is myosin II dependent, regardless of the therapy. ROCK-myosin II ablation specifically kills resistant cells via intrinsic lethal reactive oxygen species and unresolved DNA damage and limits extrinsic myeloid and lymphoid immunosuppression. Efficacy of targeted therapies and immunotherapies can be improved by combination with ROCK inhibitors.

中文翻译：

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肌球蛋白 II 再激活和细胞骨架重塑作为黑色素瘤治疗耐药性的标志和弱点。

尽管基于靶向和免疫检查点阻断的疗法在黑色素瘤中具有显着的临床益处，但不可避免地会产生耐药性。我们显示了在获得对 MAPK 抑制剂的抗性期间细胞骨架重塑以及 ROCK-肌球蛋白 II 通路表达和活性的变化。MAPK 调节肌球蛋白 II 活性，但在初始治疗反应后，耐药克隆恢复肌球蛋白 II 活性以增加存活率。高 ROCK-肌球蛋白 II 活性与侵袭性相关，可识别靶向治疗和免疫治疗耐药的黑色素瘤。无论治疗如何，耐药细胞的存活都依赖于肌球蛋白 II。ROCK-肌球蛋白 II 消融通过内在的致死活性氧和未解决的 DNA 损伤特异性杀死耐药细胞，并限制外在的骨髓和淋巴免疫抑制。