Update on the Targeted Therapy of Melanoma
Update on the Targeted Therapy of Melanoma
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DOI：
10.1007/s11864-013-0226-8
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发表时间：
2013-06-01
影响因子：
4.3
通讯作者：
Sosman, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Johnson, Douglas B.;Sosman, Jeffrey A.
黑色素瘤是最具侵袭性的皮肤恶性肿瘤，在过去的一年里，在美国造成9,000多人死亡。从历史上看，全身治疗在很大程度上是无效的，因为黑色素瘤通常对细胞毒性化疗有抗性。然而，在过去的几年里，几种靶向治疗已被证明对这种具有挑战性的疾病有效。这些最新的进展已经促进了黑色素瘤的驱动遗传畸变，特别是有丝分裂原活化蛋白激酶（MAPK）途径的突变的理解。Vemurafenib是一种BRAF抑制剂，在III期试验中显示出总体生存优势，是转移性BRAF突变型黑色素瘤一线治疗的适当选择。达拉非尼（另一种BRAF抑制剂）和曲美替尼（一种MEK抑制剂）也已在BRAF突变型黑色素瘤的III期试验中显示出有效性，并且可能作为单药治疗或联合治疗的额外治疗选择，等待监管机构的批准。此外，伊马替尼是一种很有前途的靶向治疗，用于肿瘤外显子11和13中含有KIT突变的患者。尽管这些靶向药物在转移性黑色素瘤患者中引起客观反应和临床获益，但总是会产生耐药性。迫切需要克服获得性耐药性的新目标和战略。此外，对于NRAS突变型肿瘤或具有未知驱动突变的黑色素瘤，尚未开发出有效的靶向治疗。在这篇综述中，我们讨论了目前的分子靶向治疗方案和有前途的正在进行的研究，以开发新的策略来治疗黑色素瘤。
Melanoma is the most aggressive of the cutaneous malignancies, causing more than 9,000 deaths in the past year in the United States. Historically, systemic therapies have been largely ineffective, because melanoma is usually resistant to cytotoxic chemotherapy. However, during the past few years, several targeted therapies have proved effective in this challenging disease. These recent advances have been facilitated by an improved understanding of the driving genetic aberrations of melanoma, particularly mutations in the mitogen-activated protein kinase (MAPK) pathway. Vemurafenib, a BRAF inhibitor, demonstrated an overall survival advantage in phase III trials and is an appropriate option for first-line therapy in metastatic BRAF mutant melanoma. Dabrafenib, another BRAF inhibitor, and trametinib, a MEK inhibitor, also have been shown to be effective in phase III trials for BRAF mutant melanoma and may be additional treatment options as monotherapy or in combination pending regulatory approval. Additionally, imatinib is a promising targeted therapy for patients whose tumors harbor a KIT mutation in exons 11 and 13. Although these targeted agents cause objective responses and clinical benefit in patients with metastatic melanoma, resistance invariably develops. New targets and strategies to overcome acquired resistance are urgently needed. Furthermore, no effective targeted therapy has been developed for NRAS mutant tumors or in melanomas with as yet unknown driver mutations. In this review, we discuss current molecular targeted treatment options and promising ongoing research to develop new strategies to treat melanoma.