NUAK1-Mediated Phosphorylation of NADK Mitigates ROS Accumulation to Promote Osimertinib Resistance in Non-Small Cell Lung Carcinoma.

IF 12.5 1区 医学 Q1 ONCOLOGY Cancer research Pub Date : 2024-12-02 DOI:10.1158/0008-5472.CAN-24-0249
Wei Lin, Na Wang, Shihao Wu, Mingxin Diao, Quanfu Huang, Kuo Li, Peiyuan Mei, Xiaojun Wang, Yongde Liao, Yunchong Meng
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Abstract

Osimertinib, a third generation epidermal growth factor receptor tyrosine kinase inhibitor, is approved as a first-line therapy in patients with advanced non-small cell lung carcinoma (NSCLC) with EGFR-activating mutations or the T790M resistance mutation. However, the efficacy of osimertinib is limited due to acquired resistance, highlighting the need to elucidate resistance mechanisms to facilitate the development of improved treatment strategies. Here, we screened for significantly upregulated genes encoding protein kinases in osimertinib-resistant NSCLC cells and identified NUAK1 as a pivotal regulator of osimertinib resistance. NUAK1 was highly expressed in osimertinib-resistant NSCLC and promoted the emergence of osimertinib resistance. Genetic or pharmacological blockade of NUAK1 restored the sensitivity of resistant NSCLC cells to osimertinib in vitro and in vivo. Mechanistically, NUAK1 directly interacted with and phosphorylated nicotinamide adenine dinucleotide kinase (NADK) at serine 64 (S64), which mitigated osimertinib-induced accumulation of reactive oxygen species (ROS) and contributed to the acquisition of osimertinib resistance in NSCLC. Furthermore, virtual drug screening identified T21195 as an inhibitor of NADK-S64 phosphorylation, and T21195 synergized with osimertinib to reverse acquired resistance by inducing ROS accumulation. Collectively, these findings highlight the role of the NUAK1-NADK axis in governing osimertinib resistance in NSCLC and indicate the potential of targeting this axis as a strategy for circumventing resistance. Significance: Phosphorylation of NADK by NUAK1 diminishes ROS accumulation and confers resistance to osimertinib, identifying NUAK1-NADK signaling as a potential therapeutic target for improving the response to EGFR inhibition in lung cancer.

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NUAK1 介导的 NADK 磷酸化缓解了 ROS 的积累,从而促进了非小细胞肺癌对奥希替尼的耐药性。
奥希替尼是第三代表皮生长因子受体酪氨酸激酶抑制剂,已被批准作为表皮生长因子受体激活突变或T790M耐药突变晚期非小细胞肺癌(NSCLC)患者的一线疗法。然而,奥希替尼的疗效因获得性耐药而受到限制,这凸显了阐明耐药机制以促进改良治疗策略开发的必要性。在此,我们筛选了奥希替尼耐药的NSCLC细胞中编码蛋白激酶的明显上调基因,发现NUAK1是奥希替尼耐药的关键调控因子。NUAK1在奥希替尼耐药的NSCLC中高表达,并促进了奥希替尼耐药的出现。通过基因或药物阻断NUAK1,可以在体外和体内恢复耐药NSCLC细胞对奥希替尼的敏感性。从机理上讲,NUAK1直接与NADK相互作用并使其丝氨酸64(S64)磷酸化,从而缓解了奥希替尼诱导的活性氧(ROS)积累,并促使NSCLC获得奥希替尼耐药性。此外,虚拟药物筛选发现T21195是NADK-S64磷酸化的抑制剂,T21195与奥希替尼协同作用,通过诱导ROS积累逆转获得性耐药性。总之,这些发现强调了NUAK1-NADK轴在NSCLC中调控奥希替尼耐药性的作用,并表明靶向该轴作为一种规避耐药性策略的潜力。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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