Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Cantabria, 39011 Santander, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, 28009 Madrid, Spain.
Biomolecules. 2022 Oct 26;12(11):1562. doi: 10.3390/biom12111562.
Metastatic melanoma is a highly immunogenic tumor with very poor survival rates due to immune system escape-mechanisms. Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and the programmed death-1 (PD1) receptors, are being used to impede immune evasion. This immunotherapy entails an increment in the overall survival rates. However, melanoma cells respond with evasive molecular mechanisms. ERK cascade inhibitors are also used in metastatic melanoma treatment, with the RAF activity blockade being the main therapeutic approach for such purpose, and in combination with MEK inhibitors improves many parameters of clinical efficacy. Despite their efficacy in inhibiting ERK signaling, the rewiring of the melanoma cell-signaling results in disease relapse, constituting the reinstatement of ERK activation, which is a common cause of some resistance mechanisms. Recent studies revealed that the combination of RAS-ERK pathway inhibitors and ICI therapy present promising advantages for metastatic melanoma treatment. Here, we present a recompilation of the combined therapies clinically evaluated in patients.
转移性黑色素瘤是一种高度免疫原性肿瘤，由于免疫系统逃避机制，其生存率非常低。免疫检查点抑制剂（ICI）针对细胞毒性 T 淋巴细胞相关蛋白 4（CTLA4）和程序性死亡受体 1（PD1），用于阻止免疫逃逸。这种免疫疗法增加了总体生存率。然而，黑色素瘤细胞会通过逃避分子机制做出反应。ERK 级联抑制剂也用于转移性黑色素瘤的治疗，RAF 活性阻断是主要的治疗方法，并与 MEK 抑制剂联合使用可改善许多临床疗效参数。尽管它们在抑制 ERK 信号方面具有疗效，但黑色素瘤细胞信号的重新布线导致疾病复发，从而重新激活 ERK，这是一些耐药机制的常见原因。最近的研究表明，RAS-ERK 通路抑制剂和 ICI 治疗的联合具有转移性黑色素瘤治疗的有前景的优势。在这里，我们重新编译了临床评估过的联合治疗方案。
