Mutated KRAS serves as the oncogenic driver in 30% of non-small cell lung cancers (NSCLCs) and is associated with metastatic and therapy-resistant tumors. Focal Adhesion Kinase (FAK) acts as a mediator in sustaining KRAS-driven lung tumors, and although FAK inhibitors are currently undergoing clinical development, clinical data indicated that their efficacy in producing long-term anti-tumor responses is limited. Here we revealed two FAK interactors, extracellular-signal-regulated kinase 5 (ERK5) and cyclin-dependent kinase 5 (CDK5), as key players underlying FAK-mediated maintenance of KRAS mutant NSCLC. Inhibition of ERK5 and CDK5 synergistically suppressed FAK function, decreased proliferation and induced apoptosis owing to exacerbated ROS-induced DNA damage. Accordingly, concomitant pharmacological inhibition of ERK5 and CDK5 in a mouse model of KrasG12D-driven lung adenocarcinoma suppressed tumor progression and promoted cancer cell death. Cancer cells resistant to FAK inhibitors showed enhanced ERK5-FAK signaling dampening DNA damage. Notably, ERK5 inhibition prevented the development of resistance to FAK inhibitors, significantly enhancing the efficacy of anti-tumor responses. Therefore, we propose ERK5 inhibition as a potential co-targeting strategy to counteract FAK inhibitor resistance in NSCLC.

中文翻译：

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ERK5 抑制克服了突变 KRAS 驱动的非小细胞肺癌中的 FAK 抑制剂耐药性。


突变的 KRAS 是 30% 的非小细胞肺癌 （NSCLC） 的致癌驱动因素，并与转移性和治疗性耐药性肿瘤相关。黏着斑激酶 （FAK） 在维持 KRAS 驱动的肺肿瘤中起中介作用，尽管 FAK 抑制剂目前正在进行临床开发，但临床数据表明它们在产生长期抗肿瘤反应方面的功效有限。在这里，我们揭示了两个 FAK 相互作用因子，细胞外信号调节激酶 5 （ERK5） 和细胞周期蛋白依赖性激酶 5 （CDK5），它们是 FAK 介导的 KRAS 突变型 NSCLC 维持的关键参与者。抑制 ERK5 和 CDK5 协同抑制 FAK 功能，降低增殖，并由于 ROS 诱导的 DNA 损伤加剧而诱导细胞凋亡。因此，在 KrasG12D 驱动的肺腺癌小鼠模型中，ERK5 和 CDK5 的伴随药物抑制抑制了肿瘤进展并促进了癌细胞死亡。对 FAK 抑制剂耐药的癌细胞显示出增强的 ERK5-FAK 信号传导，抑制了 DNA 损伤。值得注意的是，ERK5 抑制阻止了对 FAK 抑制剂耐药性的发展，显着增强了抗肿瘤反应的疗效。因此，我们建议将 ERK5 抑制作为一种潜在的共靶向策略，以抵消 NSCLC 中 FAK 抑制剂的耐药性。