Sullivan Ryan, LoRusso Patricia, Boerner Scott, Dummer Reinhard
From the Massachusetts General Hospital Cancer Center, Boston, MA; Yale Cancer Center, New Haven, CT; Yale University, New Haven, CT; University Hospital of Zurich, Zurich, Switzerland.
Am Soc Clin Oncol Educ Book. 2015:177-86. doi: 10.14694/EdBook_AM.2015.35.177.
The treatment of melanoma has been revolutionized over the past decade with the development of effective molecular and immune targeted therapies. The great majority of patients with melanoma have mutations in oncogenes that predominantly drive signaling through the mitogen activated protein kinase (MAPK) pathway. Analytic tools have been developed that can effectively stratify patients into molecular subsets based on the identification of mutations in oncogenes and/or tumor suppressor genes that drive the MAPK pathway. At the same time, potent and selective inhibitors of mediators of the MAPK pathway such as RAF, MEK, and ERK have become available. The most dramatic example is the development of single-agent inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) and MEK (trametinib, cobimetinib, binimetinib) for patients with metastatic BRAFV600-mutant melanoma, a subset that represents 40% to 50% of patients with metastatic melanoma. More recently, the elucidation of mechanisms underlying resistance to single-agent BRAF inhibitor therapy led to a second generation of trials that demonstrated the superiority of BRAF inhibitor/MEK inhibitor combinations (dabrafenib/trametinib; vemurafenib/cobimetinib) compared to single-agent BRAF inhibitors. Moving beyond BRAFV600 targeting, a number of other molecular subsets--such as mutations in MEK, NRAS, and non-V600 BRAF and loss of function of the tumor suppressor neurofibromatosis 1 (NF1)--are predicted to respond to MAPK pathway targeting by single-agent pan-RAF, MEK, or ERK inhibitors. As these strategies are being tested in clinical trials, preclinical and early clinical trial data are now emerging about which combinatorial approaches might be best for these patients.
在过去十年中，随着有效的分子靶向疗法和免疫靶向疗法的发展，黑色素瘤的治疗发生了革命性变化。绝大多数黑色素瘤患者的癌基因发生突变，这些突变主要通过丝裂原活化蛋白激酶（MAPK）途径驱动信号传导。现已开发出分析工具，可根据驱动MAPK途径的癌基因和/或肿瘤抑制基因中的突变，有效地将患者分层为分子亚组。与此同时，MAPK途径介质（如RAF、MEK和ERK）的强效和选择性抑制剂已可供使用。最显著的例子是，针对转移性BRAFV600突变黑色素瘤患者（该亚组占转移性黑色素瘤患者的40%至50%）开发了BRAF（维莫非尼、达拉非尼、恩考芬尼）和MEK（曲美替尼、考比替尼、比美替尼）的单药抑制剂。最近，对单药BRAF抑制剂治疗耐药机制的阐明促成了第二代试验，该试验表明BRAF抑制剂/MEK抑制剂联合用药（达拉非尼/曲美替尼；维莫非尼/考比替尼）优于单药BRAF抑制剂。除了靶向BRAFV600，预计其他一些分子亚组——如MEK、NRAS和非V600 BRAF突变以及肿瘤抑制基因神经纤维瘤病1（NF1）功能丧失——对单药泛RAF、MEK或ERK抑制剂靶向MAPK途径有反应。随着这些策略在临床试验中得到检验，关于哪些联合治疗方法可能最适合这些患者的临床前和早期临床试验数据正在出现。
