英国伦敦玛丽女王大学Victoria Sanz-Moreno和Jose L. Orgaz合作发现，肌球蛋白II激活和细胞骨架重塑是造成黑素瘤治疗耐药性的原因。2020年1月13日出版的《癌细胞》发表了这一最新研究成果。

研究人员发现在抗MAPK抑制剂的细胞中会发生细胞骨架重塑、基因表达改变以及ROCK-肌球蛋白II途径活性的变化。MAPK调节肌球蛋白II的活性，但是在最初的治疗反应后，耐药克隆恢复肌球蛋白II的活性以增加存活率。ROCK-肌球蛋白II的高活性与肿瘤恶性程度相关，以此可鉴别靶向治疗和免疫治疗耐药的黑色素瘤。无论哪种治疗方法，耐药细胞的存活均依赖于肌球蛋白II。ROCK-肌球蛋白II缺失可产生致死量的活性氧和DNA损伤修复缺失从而特异性杀死耐药细胞，并限制外源性髓样和淋巴样免疫抑制。 与ROCK抑制剂联合使用可提高靶向疗法和免疫疗法的疗效。

据介绍，尽管靶向治疗和基于免疫检查点封锁的疗法在临床上对黑色素瘤的治疗具有益处，但不可避免地也存在耐药性问题。

附：英文原文

Title: Myosin II Reactivation and Cytoskeletal Remodeling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance

Author: Jose L. Orgaz, Eva Crosas-Molist, Amine Sadok, Anna Perdrix-Rosell, Oscar Maiques, Irene Rodriguez-Hernandez, Jo Monger, Silvia Mele, Mirella Georgouli, Victoria Bridgeman, Panagiotis Karagiannis, Rebecca Lee, Pahini Pandya, Lena Boehme, Fredrik Wallberg, Chris Tape, Sophia N. Karagiannis, Ilaria Malanchi, Victoria Sanz-Moreno

Issue&Volume: 2020/01/13

Abstract: 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.

DOI: 10.1016/j.ccell.2019.12.003

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(19)30573-2