摘要
最近几年,通过使用小分子抑制剂抵抗BRAF (V600E 突变)的活化和激活MEK1/2,借助RAS-RAF-MEK-ERK的细胞内信号传递被成功用作黑素瘤的新治疗方法。并且突变的c-KIT已经被确定为一个潜在靶标。同时,有证据表明联合BRAF抑制剂和MEK1/2抑制剂得到的效果要优于单个药物的治疗效果。更重要的是,新的治疗策略证实依次采用BRAF抑制剂和新开发的针对常见的T淋巴表明抗原4(CTLA-4)或者是细胞程序性死亡受体1 (PD-1)的免疫疗法。深入的分子分析发现新的治疗中的耐药性和复发的新机制,这些将影响到未来治疗方案的确定。而且,下一代基因测序数据显示复发的损伤区域具有特异的遗传畸形。同时,高通量的黑素瘤测序研究揭示了一系统的新的治疗候选药物用于进一步治疗方法,如ERBB4、GRIN2A、GRM3和RAC1。近期更多的生物信息学技术提供遗传的证明了肿瘤的异质多样性和实体肿瘤的肿瘤克隆性,这同样有可能与黑素瘤相关。但是这些技术还没有应用到这个肿瘤中。在本综述中,对当前黑素瘤治疗的遗传基础、治疗的耐药性和复发进行了详细地回顾,包括基于最近高通量测序数据提出的新的治疗方法。而且,未来的基于每个患者自身突变情况的个体治疗也被讨论。
关键词: BRAF,遗传,免疫治疗,靶向治疗。
Current Drug Targets
Title:The Genetic Basis of New Treatment Modalities in Melanoma
Volume: 16 Issue: 3
Author(s): Manfred Kunz
Affiliation:
关键词: BRAF,遗传,免疫治疗,靶向治疗。
摘要: In recent years, intracellular signal transduction via RAS-RAF-MEK-ERK has been successfully targeted in new treatment approaches for melanoma using small molecule inhibitors against activated BRAF (V600E mutation) and activated MEK1/2. Also mutated c-KIT has been identified as a promising target. Meanwhile, evidence has been provided that combinations between BRAF inhibitors and MEK1/2 inhibitors are more promising than single-agent treatments. Moreover, new treatment algorithms favor sequential treatment using BRAF inhibitors and newly developed immunotherapies targeting common T lymphocyte antigen 4 (CTLA-4) or programmed cell death 1 (PD-1). In depth molecular analyses have uncovered new mechanisms of treatment resistance and recurrence, which may impact on future treatment decisions. Moreover, next-generation sequencing data have shown that recurrent lesions harbor specific genetic aberrations. At the same time, high throughput sequencing studies of melanoma unraveled a series of new treatment candidates for future treatment approaches such as ERBB4, GRIN2A, GRM3, and RAC1. More recent bioinformatic technologies provided genetic evidence for extensive tumor heterogeneity and tumor clonality of solid tumors, which might also be of relevance for melanoma. However, these technologies have not yet been applied to this tumor. In this review, an overview on the genetic basis of current treatment of melanoma, treatment resistance and recurrences including new treatment perspectives based on recent high-throughput sequencing data is provided. Moreover, future aspects of individualized treatment based on each patient’s individual mutational landscape are discussed.
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Cite this article as:
Manfred Kunz , The Genetic Basis of New Treatment Modalities in Melanoma, Current Drug Targets 2015; 16 (3) . https://dx.doi.org/10.2174/1389450116666150204112138
DOI https://dx.doi.org/10.2174/1389450116666150204112138 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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