NRAS突变型晚期黑色素瘤的治疗进展

Advances in the treatment of advanced melanoma with NRAS gene mutation

黑色素瘤的发生、发展与多种癌基因的激活密切相关。15%~20%的黑色素瘤患者存在NRAS基因的激活突变,携带该突变基因的黑色素瘤具有更强的侵袭性,治疗难度大。由于RAS蛋白突变位点属于弱药物靶标,目前尚缺乏有效的靶向抑制剂,因此临床上多以免疫检查点抑制剂作为NRAS突变型晚期黑色素瘤的一线治疗方案,然而治疗反应率较低。近年来,在NRAS突变亚型中靶向治疗方案的探索主要集中在NRAS下游丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)通路,但结果不一:新型MEK1/2抑制剂tunlametinib,在晚期NRAS突变患者中总体客观缓解率(objective response rate,ORR)达到34.7%,较既往的binimetinib显著提高;然而泛RAF抑制剂belvarafenib和ERK抑制剂ulixertinib的Ⅰ期临床试验却未能展示出该药明显的优势。此外,以MEK抑制剂为基础的联合治疗也取得一定进展,现有证据表明,分子抑制剂类药物较免疫检查点抑制剂显示出更多的优势:选择性BRAF/CRAF抑制剂naporafenib(LXH254)与MEK抑制剂trametinib联合治疗NRAS突变型黑色素瘤的Ⅰb期临床试验中ORR达到46.7%;细胞周期蛋白依赖性激酶4/6(cyclindependent kinase4/6,CDK4/6)抑制剂ribociclib和binimetinib联合治疗在携带NRAS突变同时合并细胞周期蛋白基因异常的人群中可达32.5%;黏着斑激酶(focal adhesion kinase,FAK)抑制剂IN10018联合cobimetinib的研究结果也表现出较好的ORR(38.5%);但免疫检查点抑制剂程序性死亡[蛋白]配体-1(programmed death ligand-1,PD-L1)单抗durvalumab联合trametinib方案仅使27.2%的患者达到部分缓解(3/11)。与此同时,部分临床前研究结果也显示出一些转化潜质:如热激蛋白90(heat shock protein 90,HSP90)抑制剂XL888和丝氨酸/苏氨酸蛋白激酶19(serine/threonine protein kinase 19,STK19)抑制剂均在动物模型中表现出显著抑制NRAS突变型黑色素瘤细胞生长的能力。本文综述了NRAS突变型黑色素瘤的致癌机制及近年来治疗领域的研究进展,旨在展示该亚型患者的治疗现状,对多种新型治疗方法的临床研究结果进行总结和归纳,为当前临床实践和未来联合治疗方案提供依据。

Oncogenic mutations are responsible for a majority of the malignancy of melanoma.Activating mutations of NRAS gene are found in 15%-20%melanoma cases,endowing the tumor cells with more aggressive phenotypes and greater difficulty to treat.The development of targeted inhibitor of mutant NRAS remains a big challenge since the mutation sites could hardly be druggable.Therefore,immune checkpoint inhibitors are currently recommended as the first-line therapy for NRAS mutant advanced melanoma albeit the response rate is still far from satisfaction.In recent years,the exploration of targeted therapy regimens has focused on the downstream pathway of NRAS,the mitogen-activated protein kinase(MAPK)pathway.A novel MEK1/2 inhibitor tunlametinib was reported to achieve an objective response rate(ORR)of 34.7%which is higher than the ORR of binimetinib in previous report.However,the phaseⅠtrial of the pan-RAF inhibitor belvarafenib and the ERK inhibitor ulixertinib failed to show marked benefits.In the meanwhile,MEK inhibitor-based combination therapy has also achieved some progress:it was reported in the phaseⅠb trial of the selective BRAF/CRAF inhibitor naporafenib(LXH254)combined with Trametinib in NRAS mutant melanoma that the ORR was 46.7%.The ORR of binetinib plus the cyclin-dependent kinase 4/6(CDK4/6)inhibitor,ribociclib,was 32.5%in patients with NRAS mutation with concurrent alterations of CDKN2A,CDK4,or CCND1.The response rate of the combination of focal adhesion kinase(FAK)inhibitor,IN10018,and cobimetinib was 38.5%.On the other hand,only 27.2%of patients carrying NRAS mutation responded partially to the combined regimen of immune checkpoint inhibitor programmed death ligand-1(PD-L1)monoclonal antibody durvalumab+trametinib.In addition,some preclinical findings have also shown translational potentials:for example,heat shock protein 90(HSP90)inhibitor XL888 and serine/threonine protein kinase 19(STK19)inhibitors were found to inhibit the growth of NRAS mutant melanoma in animal models.This article reviewed the oncogenic roles of NRAS mutation in melanoma and the cutting-edge clinical trials for the treatment of NRAS mutant melanoma,aiming to provide alterative treatment options for clinical practice and inspire novel combination regimen.