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利用YES1驱动的EGFR表达提高了EGFR抑制剂的有效性

Leslie Cuellar-Vite^1,2,3, Elyse M Donaubauer¹, Kristen L Weber-Bonk²

¹Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.

Molecular cancer research : MCR

|January 23, 2025

概括

YES1提高表皮生长因子受体 (EGFR) 水平,推动癌症的生长. 阻断YES1增强了EGFR抑制剂在各种癌症中的有效性,包括三阴性乳腺癌和非小细胞肺癌.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
癌症治疗方法癌症治疗方法

背景情况:

表皮生长因子受体 (EGFR) 是许多癌症的关键驱动因素,但EGFR抑制剂 (EGFRi) 受到剂量限制性毒性和特定突变有效性的限制.
目前的EGFR抑制剂治疗主要针对激酶活性,留下潜在的治疗途径未被探索.

研究的目的:

研究YES1作为治疗点,通过减少EGFR转录来扩大EGFR抑制剂的疗效.
探索YES1在调节三阴性乳腺癌 (TNBC) 和非小细胞肺癌 (NSCLC) 中EGFR表达的作用.

主要方法:

研究了YES1在TNBC中的表达及其对EGFR水平的影响.
阐明了通过YES1影响EGFR表达的信号通路 (YES1 -> JNK -> c-Jun -> EGFR).
在体外和体外癌症模型中评估了YES1阻断与EGFR抑制剂的协同效应.

主要成果:

在TNBC中YES1的表达很高,通过增加EGFR水平来促进细胞生长.
通过JNK传递的YES1信号稳定了AP-1转录因子c-Jun,导致EGFR表达升高.
YES1在NSCLC中维持EGFR表达,包括具有T790M突变的模型.
对YES1和EGFR抑制剂的联合阻断在TNBC和NSCLC模型中表现出协同效果,无论EGFR突变如何.

结论:

YES1在维持野生类型和突变EGFR表达方面发挥着关键作用,呈现出一种新的治疗点.
阻断YES1活性提供了一种策略,以提高EGFR抑制剂在更广泛的癌症中有效性,包括那些通常对当前治疗不耐药的癌症.
向YES1可以降低EGFR抑制剂疗效的门,扩大各种EGFR驱动的恶性瘤的治疗选择.

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