在精密瘤学中解码耐药性的模型:在胆管癌瘤中对FGFR抑制剂的获得耐药性
L Goyal1, D DiToro2, F Facchinetti3
1Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, USA; Department of Medicine, Stanford Cancer Center, Stanford University School of Medicine, Palo Alto, USA.
概括
在胆管癌中对纤维细胞生长因子受体 (FGFR) 抑制剂的获得性耐药性是复杂的,由多种突变驱动. 了解这些抵抗机制是开发更有效的下一代FGFR抑制剂的关键.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 纤维细胞生长因子受体 (FGFR) 抑制剂为FGFR改变的胆管癌提供了改善的结果.
- 对这些向疗法的获得性耐药性限制了长期疗效.
- 对抗性模式的全面表征对于推进治疗至关重要.
研究的目的:
- 描述胆管癌中对FGFR抑制剂获得的耐药性的多样性,克隆性,频率和机制.
- 整合多式联运数据,以更深入地了解耐药生物学.
- 为下一代FGFR抑制剂的设计提供信息.
主要方法:
- 来自无细胞DNA,组织活检,快速尸检,统计基因组学,体外/体内研究和药理学的综合数据.
- 来自10个机构的临床样本的纵向分析.
- 描述FGFR2激酶域突变和抵抗机制.
主要成果:
- 在77名符合条件的患者中鉴定出26种不同的FGFR2激酶域突变,其中63%的患者患有多种.
- 在具有临床益处的患者中,FGFR2激酶域突变显着更高.
- 多克隆性耐药性可能是由低度的药物驱动的,其中分子制动和守门员突变占主导地位.
结论:
- 开发了一种获得性耐药性生物学模型,以指导下一代FGFR抑制剂的设计.
- 下一代抑制剂应该是小的,高亲和度的,有选择性的.
- 丁宁替尼在临床前和临床上对关键耐药性突变表现出活性,为未来的研究提供了蓝图.
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