突变的 KRAS 是 30% 的非小细胞肺癌 (NSCLC) 的致癌驱动因素，并与转移性和治疗耐药性肿瘤相关。粘着斑激酶 (FAK) 充当维持 KRAS 驱动的肺部肿瘤的介质，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产生长期抗肿瘤反应的功效有限。在这里，我们揭示了两种 FAK 相互作用因子，即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 NSCLC 维持的关键参与者。抑制 ERK5 和 CDK5 可协同抑制 FAK 功能，减少增殖并诱导细胞凋亡，因为 ROS 诱导的 DNA 损伤加剧。因此，在 KrasG12D 驱动的肺腺癌小鼠模型中，同时药理学抑制 ERK5 和 CDK5 可抑制肿瘤进展并促进癌细胞死亡。对 FAK 抑制剂具有抗性的癌细胞表现出增强的 ERK5-FAK 信号传导，可抑制 DNA 损伤。值得注意的是，ERK5 抑制可防止对 FAK 抑制剂产生耐药性，从而显着增强抗肿瘤反应的功效。因此，我们建议 ERK5 抑制作为一种潜在的共同靶向策略，以抵消 NSCLC 中的 FAK 抑制剂耐药性。© 2024。作者。

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.© 2024. The Author(s).