不可逆转的FGFR抑制剂KIN-3248克服了FGFR2激酶域突变
Eranga R Balasooriya1,2, Qibiao Wu1,2, Haley Ellis1,2
1Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts.
概括
一种新的FGFR抑制剂,KIN-3248,有效地向FGFR2和FGFR3突变,包括引起耐药性的守门者突变. 这为治疗肝内胆管癌和其他由FGFR驱动的癌症提供了潜力.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 药物发现 药物发现 药物发现
背景情况:
- 纤维细胞生长因子受体 (FGFRs) 经常被激活在诸如肝内胆管癌 (ICC) 和膀癌等癌症中.
- 已批准的FGFR氨酸激酶抑制剂 (TKIs) 面临由于二次激酶域突变的耐药性,限制了治疗疗效.
研究的目的:
- 描述KIN-3248的临床前活性,这是下一代共价泛FGFR抑制剂.
- 评估KIN-3248与FGFR2和FGFR3突变的对抗,包括那些对现有疗法产生耐药性的突变.
主要方法:
- 在体外和体内临床前模型的FGFR2融合阳性ICC与二次激酶域突变.
- 在膀癌模型中测试特定的FGFR3等位基因.
- 评估KIN-3248对各种FGFR2和FGFR3突变的活性,包括守门员突变.
主要成果:
- KIN-3248对FGFR1-3表现出强大的选择性,并保留了对多个FGFR2激酶域突变的活性.
- 该抑制剂对FGFR3突变 (V555M,N540K) 和FGFR2 V565F守门员突变有效,这是一个关键的抵抗机制.
- 与EGFR或MEK抑制剂的联合疗法在体内增强了KIN-3248的疗效.
结论:
- KIN-3248是一种新型的FGFR1-4抑制剂,具有针对FGFR激酶域突变的独特活性.
- 它克服抗药性突变的能力突显了其对ICC和其他FGFR驱动的恶性瘤的潜在治疗价值.
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