激活EGFR会限制肝癌对伦瓦替尼的反应
Haojie Jin1,2, Yaoping Shi3, Yuanyuan Lv1
1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
在治疗晚期肝细胞癌 (HCC) 方面,使用林瓦提尼与表皮生长因子受体 (EGFR) 抑制剂结合使用具有前景. 这种组合疗法为患有高EGFR水平的晚期肝癌患者提供了一种新策略.
科学领域:
- 癌症学
- 分子生物学
- 遗传学
背景情况:
- 肝细胞癌 (HCC) 是一种具有有限治疗选择的侵袭性肝癌.
- 伦瓦替尼是一种多位激酶抑制剂,在晚期HCC中具有适度的临床益处.
- 确定新的治疗策略对于改善HCC患者的治疗结果至关重要.
研究的目的:
- 确定肝细胞癌 (HCC) 的新疗法目标和组合.
- 研究伦瓦替尼与其他向治疗在肝癌中的合成致死性.
- 评估连合林瓦提尼与表皮生长因子受体 (EGFR) 抑制剂的疗效.
主要方法:
- 用基因组为中心的CRISPR- Cas9基因查来确定与伦瓦替尼的合成致死性相互作用.
- 在体外和体内实验中评估了lenvatinib和gefitinib在肝癌模型中的抗增殖作用.
- 一项临床试验 (NCT04642547) 评估了晚期HCC患者的组合治疗.
主要成果:
- 伦瓦替尼在肝癌中被发现是合成致命的EGFR抑制.
- 伦瓦提尼布和盖菲提尼布的组合在体外和体内表现出强大的抗繁殖作用.
- 在机制上,EGFR抑制阻断了lenvatinib诱导的EGFR-PAK2-ERK5轴的反激活.
- 临床治疗没有对lenvatinib反应的晚期HCC患者的组合治疗产生了有意义的反应.
结论:
- 伦瓦替尼与格菲替尼的结合是晚期HCC的有前途的治疗策略.
- 这种组合特别适用于约50%的高EGFR水平的HCC患者.
- 向EGFR-PAK2-ERK5轴为克服肝癌中的伦瓦替尼抗性提供了一种新方法.
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