在黑色素瘤中抗 BRAF 抑制剂的分子基础:系统性审查
Ilaria Cosci1, Valentina Salizzato2, Paolo Del Fiore3
1Unit of Andrology and Reproductive Medicine, Department of Medicine, University of Padova, 35122 Padova, Italy.
Pharmaceuticals (Basel, Switzerland)
|August 28, 2025
概括
针对黑色素瘤中的BRAF突变可以改善结果,但耐药性很常见. 本综述详细介绍了对BRAF抑制剂的原发性,适应性和获得性耐药性机制,并讨论了克服它们的策略.
科学领域:
- 癌症学
- 分子生物学
- 皮肤病学
背景情况:
- 黑色素瘤是一种致命的皮肤癌,通常具有激活MAPK通路的BRAF突变 (例如V600E).
- BRAF 抑制剂 (BRAFi) 和 MEK 抑制剂 (MEKi) 改善了 BRAF V600 突变黑色素瘤的治疗结果.
- 治疗耐药性仍然是晚期黑色素瘤治疗的重大临床挑战.
研究的目的:
- 对黑色素瘤BRAF向治疗的治疗耐药性机制进行审查和分类.
- 分析原发性,适应性和获得性抗性的分子基础.
- 突出克服耐药性和改善患者结果的新战略.
主要方法:
- 整合了针对BRAF治疗的临床前和临床研究的文献评论.
- 抗性的分类为初级,适应性和获得性形式.
- 对遗传/表观遗传变化的分析,路径的重新激活和微环境相互作用.
主要成果:
- 主要耐药性涉及先前存在的改变,激活像PI3K-AKT这样的替代途径.
- 适应性/获得性耐药性包括二次BRAF突变,路径冗余,表型切换和肌体/免疫相互作用.
- 高通量测序发现了对耐药性的NRAS,NF1和PTEN变化.
结论:
- 了解各种抗药机制对于晚期黑色素瘤治疗至关重要.
- 组合疗法,代谢向和生物标志物是克服耐药性的关键策略.
- 这一综述为未来的治疗发展和黑色素瘤的精确瘤学提供了信息.
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