Cheng Yabin, Zhang Guohong, Li Gang
Department of Dermatology and Skin Science, Research Pavilion, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, BC, Canada.
Cancer Metastasis Rev. 2013 Dec;32(3-4):567-84. doi: 10.1007/s10555-013-9433-9.
New drugs targeting the mitogen-activated protein kinase (MAPK) pathway have generated striking clinical response in melanoma therapy. From the discovery of BRAF mutation in melanoma in 2002, to the approval of first BRAF inhibitor vemurafenib for melanoma treatment by the US Food and Drug Administration in 2011, therapies targeting the MAPK pathway have been proven effective in less than a decade. The success of vemurafenib stimulated more intensive investigation of the molecular mechanisms of melanoma pathogenesis and development of new treatment strategies targeting specific molecules in MAPK pathway. Although selective BRAF inhibitors and MEK inhibitors demonstrated improved overall survival of metastatic melanoma patients, limited duration or development of resistance to BRAF inhibitors have been reported. Patients with metastatic melanoma still face very poor prognosis and lack of clarified therapies. Studies and multiple clinical trials on more potent and selective small molecule inhibitory compounds to further improve the clinical effects and overcome drug resistance are underway. In this review, we analyzed the therapeutic potentials of each member of the MAPK signaling pathway, summarized important MAPK-inhibiting drugs, and discussed the promising combination treatment targeting multiple targets in melanoma therapy, which may overcome the drawbacks of current drugs treatment.
靶向丝裂原活化蛋白激酶（MAPK）通路的新型药物在黑色素瘤治疗中产生了显著的临床反应。从2002年黑色素瘤中BRAF突变的发现，到2011年美国食品药品监督管理局批准首个用于黑色素瘤治疗的BRAF抑制剂维莫非尼，靶向MAPK通路的疗法在不到十年的时间里被证明是有效的。维莫非尼的成功激发了对黑色素瘤发病机制分子机制的更深入研究，以及针对MAPK通路中特定分子的新治疗策略的开发。尽管选择性BRAF抑制剂和MEK抑制剂显示出转移性黑色素瘤患者总生存期的改善，但已报道BRAF抑制剂的持续时间有限或出现耐药性。转移性黑色素瘤患者的预后仍然很差，且缺乏明确的治疗方法。目前正在进行关于更有效和选择性小分子抑制化合物的研究及多项临床试验，以进一步提高临床疗效并克服耐药性。在本综述中，我们分析了MAPK信号通路各成员的治疗潜力，总结了重要的MAPK抑制药物，并讨论了在黑色素瘤治疗中靶向多个靶点的有前景的联合治疗方法，这可能克服当前药物治疗的缺点。
