对抗癌症激酶抑制剂的增长因子驱动的耐药性广泛存在潜力
Timothy R Wilson1, Jane Fridlyand, Yibing Yan
1Research Oncology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA.
癌细胞可以通过激活替代生存途径来发展耐药性. 用特定的配体准受体氨酸激酶 (RTKs),如BRAF抑制剂耐药黑色素瘤的HGF,可以克服这种耐药性.
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 是一个学科.
背景情况:
- 激酶抑制剂是临床验证的癌症药物标.
- 药物耐药性,无论是先天的还是获得的,限制了激酶抑制剂的疗效.
- 抵抗通常涉及激活多余的细胞生存信号,特别是通过受体氨酸激酶 (RTKs).
研究的目的:
- 调查冗余受体氨酸激酶 (RTK) 信号传导在赋予对激酶抑制剂耐药性的作用.
- 为了确定特定的RTK配体,可以克服癌症细胞系中的耐药性.
- 探索RTK介导的耐药机制的临床影响.
主要方法:
- 利用了一个基因酶上的人类癌症细胞系的面板.
- 将癌细胞暴露在各种RTK配体中,以评估从药物敏感性中获救.
- 研究了肝细胞生长因子 (HGF) 对用BRAF抑制剂PLX4032 (威穆拉芬尼布) 治疗的BRAF突变黑色素瘤细胞的影响.
主要成果:
- 大多数经过测试的癌细胞系可以通过暴露在RTK配体中,从激酶抑制剂敏感性中获救.
- 肝细胞生长因子 (HGF) 在BRAF突变黑色素瘤细胞中赋予了对BRAF抑制剂PLX4032 (vemurafenib) 的抗性.
- 在癌细胞内的RTK转换信号通路中显示出广泛的冗余性.
结论:
- 受体氨酸激酶 (RTK) 配体在对酶向癌症药物的先天性和获得性耐药性中起着重要作用.
- RTK信号通路的冗余性对实现对激酶抑制剂的持久反应提出了广泛的挑战.
- 针对RTK信号的策略可能对克服各种癌症的耐药性至关重要.
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