ERK5 suppression overcomes FAK inhibitor resistance in mutant KRAS-driven non-small cell lung cancer.

IF 9 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EMBO Molecular Medicine Pub Date : 2024-09-13 DOI:10.1038/s44321-024-00138-7
Chiara Pozzato,Gonçalo Outeiro-Pinho,Mirco Galiè,Giorgio Ramadori,Georgia Konstantinidou
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Abstract

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.
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抑制 ERK5 可克服突变 KRAS 驱动的非小细胞肺癌对 FAK 抑制剂的耐药性。
在 30% 的非小细胞肺癌(NSCLC)中,突变的 KRAS 是致癌驱动因素,并与转移性和耐药性肿瘤有关。病灶粘附激酶(FAK)是维持KRAS驱动的肺部肿瘤的介质,尽管FAK抑制剂目前正在临床开发中,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介导的维持KRAS突变型NSCLC的关键因素。抑制ERK5和CDK5可协同抑制FAK功能,减少增殖,并因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,同时药物抑制 ERK5 和 CDK5 可抑制肿瘤进展并促进癌细胞死亡。对FAK抑制剂具有抗药性的癌细胞显示出增强的ERK5-FAK信号抑制DNA损伤。值得注意的是,ERK5抑制能阻止FAK抑制剂耐药性的产生,显著提高抗肿瘤反应的疗效。因此,我们建议将ERK5抑制作为一种潜在的联合靶向策略,以对抗NSCLC中的FAK抑制剂耐药性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
EMBO Molecular Medicine
EMBO Molecular Medicine 医学-医学:研究与实验
CiteScore
17.70
自引率
0.90%
发文量
105
审稿时长
4-8 weeks
期刊介绍: EMBO Molecular Medicine is an open access journal in the field of experimental medicine, dedicated to science at the interface between clinical research and basic life sciences. In addition to human data, we welcome original studies performed in cells and/or animals provided they demonstrate human disease relevance. To enhance and better specify our commitment to precision medicine, we have expanded the scope of EMM and call for contributions in the following fields: Environmental health and medicine, in particular studies in the field of environmental medicine in its functional and mechanistic aspects (exposome studies, toxicology, biomarkers, modeling, and intervention). Clinical studies and case reports - Human clinical studies providing decisive clues how to control a given disease (epidemiological, pathophysiological, therapeutic, and vaccine studies). Case reports supporting hypothesis-driven research on the disease. Biomedical technologies - Studies that present innovative materials, tools, devices, and technologies with direct translational potential and applicability (imaging technologies, drug delivery systems, tissue engineering, and AI)
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