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针对EGFR的抗体促进HER2ADC的内部化和疗效

Avantika Gupta¹, Flavia Michelini¹, Hong Shao¹

¹Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Cell reports. Medicine

|October 22, 2024

概括

表皮生长因子受体 (EGFR) 的过度表达可能会限制T-DXd在HER2阳性癌症中的有效性. 向EGFR可以通过改善药物内部化和有效载荷释放来恢复T-DXd的有效性.

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:

特拉斯图祖马布德鲁克斯泰干 (T-DXd) 在HER2阳性癌症中显示出显著的疗效.
然而,对T-DXd的治疗反应是可变的,即使在HER2表达瘤中也是如此.
HER2受体内部化和有效载荷释放对于T-DXd活动至关重要,但可能取决于环境.

研究的目的:

调查表皮生长因子受体 (EGFR) 在调节T-DXd贩运和疗效中的作用.
为了确定EGFR是否影响HER2受体内部化和随后的有效载荷释放.
探索克服EGFR介导的T-DXd耐药性的治疗策略.

主要方法:

评估了EGFR表达水平对HER2/T-DXd复合体内化的影响.
利用EGFR敲除和EGFR单克隆抗体来调节EGFR的活性.
在临床前模型中评估了T-DXd贩运和抗瘤活性的恢复.

主要成果:

过高的EGFR表达促进了EGFR/HER2异构体的形成,阻碍了T-DXd内部化.
过度表达EGFR抑制T-DXd的吸收,并降低其抗瘤功效.
通过对EGFR内细胞的抑制或药理刺激,可以恢复体内T-DXd的贩运和活性.

结论:

在HER2阳性癌症中,EGFR过度表达代表了对T-DXd的新型抗药机制.
针对EGFR的组合策略可以克服EGFR介导的T-DXd耐药性.
调节EGFR贩运提供了一种潜在的治疗方法,以提高T-DXd的有效性.

关键词:

在ADC内部化过程中,ADC内部化由于EGFR的过度表达,有HER2阳性癌症的癌症.电阻T-DXd 的电阻T-DXd 的电阻

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