在FGFR2-驱动的恶性瘤中了解和克服对选择性FGFR抑制剂的抵抗
Francesco Facchinetti1, Yohann Loriot1,2,3, Floriane Brayé1
1Université Paris-Saclay, Gustave Roussy, Inserm U981, Villejuif, France.
在FGFR2驱动癌症中对FGFR抑制剂的耐药性显示出显著的分子多样性,特别是在胆管癌中. 顺序的,有针对性的治疗可以克服这种抵抗,改善患者的治疗结果.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 遗传学 遗传学 是一个
背景情况:
- 纤维细胞生长因子受体2 (FGFR2) 改变驱动各种恶性瘤,包括胆管癌.
- 选择性FGFR抑制剂提供向治疗,但获得的耐药性限制了长期疗效.
- 了解耐药机制对于开发有效的治疗策略至关重要.
研究的目的:
- 研究FGFR2驱动恶性瘤患者对选择性FGFR抑制剂获得的耐药性的分子机制.
- 分析耐药性突变的异质性,并确定潜在的治疗漏洞.
主要方法:
- 分析循环瘤DNA (ctDNA) 和来自FGFR2变异在泛FGFR抑制剂上进展的患者的组织活检.
- 采用了全外因子测序和针对性下一代测序.
- 使用FGFR2::BICC1 Ba/F3和患者衍生异种移植 (PDX) 模型进行功能验证.
主要成果:
- 观察到高的患者内和患者间分子异质性,特别是胆管癌 (14/27名患者) 中多克隆FGFR2激酶域突变,对可逆和不可逆的抑制剂都具有耐药性.
- 其他瘤类型的多克隆性较少. 抵抗突变的目标是N550和V565.5等关键残留物.
- 在PI3K/mTOR和MAPK途径的非目标变化是常见的. 不可逆的抑制剂对FGFR2突变表现出更好的活性,而lirafugratinib对V565突变有效.
结论:
- 由FGFR2驱动的恶性瘤在进展到FGFR抑制剂时表现出显著的分子异质性.
- 顺序的,分子引导的治疗策略有望克服这些瘤的抗性.
- 向治疗,包括不可逆转的抑制剂和特定途径的药物,可以有效地控制耐药性.
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