Mechanisms of Drug Resistance in Melanoma
Mechanisms of Drug Resistance in Melanoma
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DOI：
10.1007/164_2017_17
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发表时间：
2018-01-01
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影响因子：
--
通讯作者：
Viros, Amaya
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文献类型：
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作者：
Winder, Matthew;Viros, Amaya
转移性黑色素瘤与不良结局相关，并且在很大程度上对历史标准治疗无效。近年来，靶向小分子抑制剂和免疫疗法的发展彻底改变了这些患者的护理并提高了其总体生存率。靶向BRAF和MEK以阻断促分裂原活化蛋白激酶（MAPK）途径的疗法是第一个显示出前所未有的临床反应的疗法。在这些令人鼓舞的结果之后，靶向免疫检查点抑制分子细胞毒性T淋巴细胞相关抗原4（CTLA-4）、程序性细胞死亡（PD）-1和PD-配体1（PD-L1）的抗体通过实现抗肿瘤免疫应答，在一个重要的患者亚组中证明了持续的肿瘤消退。尽管在实践中发生了这些里程碑式的变化，但大多数患者对MAPK通路抑制剂和免疫检查点阻断治疗具有内在耐药性或快速获得耐药性。缺乏反应可能是由肿瘤细胞中的突变和非突变事件以及周围肿瘤微环境的变化驱动的。常见的耐药机制绕过了肿瘤细胞在靶向治疗期间对初始MAPK通路驱动突变的依赖，并允许逃避宿主免疫系统以允许黑色素瘤在免疫治疗后生长和存活。这凸显了对考虑患者特定遗传和免疫学特征的个性化治疗方案的要求。在这里，我们审查的机制，黑色素瘤显示内在的阻力或获得耐药的靶向治疗和免疫治疗。
Metastatic melanoma is associated with poor outcome and is largely refractory to the historic standard of care. In recent years, the development of targeted small-molecule inhibitors and immunotherapy has revolutionised the care and improved the overall survival of these patients. Therapies targeting BRAF and MEK to block the mitogen-activated protein kinase (MAPK) pathway were the first to show unprecedented clinical responses. Following these encouraging results, antibodies targeting immune checkpoint inhibition molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death (PD)-1, and PD-ligand1(PD-L1) demonstrated sustained tumour regression in a significant subset of patients by enabling an anti-tumour immunologic response. Despite these landmark changes in practice, the majority of patients are either intrinsically resistant or rapidly acquire resistance to MAPK pathway inhibitors and immune checkpoint blockade treatment. The lack of response can be driven by mutations and non-mutational events in tumour cells, as well as by changes in the surrounding tumour microenvironment. Common resistance mechanisms bypass the dependence of tumour cells on initial MAPK pathway driver mutations during targeted therapy, and permit evasion of the host immune system to allow melanoma growth and survival following immunotherapy. This highlights the requirement for personalised treatment regimens that take into account patient-specific genetic and immunologic characteristics. Here we review the mechanisms by which melanomas display intrinsic resistance or acquire resistance to targeted therapy and immunotherapy.