Wei Lin, Na Wang, Shihao Wu, Mingxin Diao, Quanfu Huang, Kuo Li, Peiyuan Mei, Xiaojun Wang, Yongde Liao, Yunchong Meng
{"title":"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。","authors":"Wei Lin, Na Wang, Shihao Wu, Mingxin Diao, Quanfu Huang, Kuo Li, Peiyuan Mei, Xiaojun Wang, Yongde Liao, Yunchong Meng","doi":"10.1158/0008-5472.CAN-24-0249","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":" ","pages":"4081-4098"},"PeriodicalIF":12.5000,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"NUAK1-Mediated Phosphorylation of NADK Mitigates ROS Accumulation to Promote Osimertinib Resistance in Non-Small Cell Lung Carcinoma.\",\"authors\":\"Wei Lin, Na Wang, Shihao Wu, Mingxin Diao, Quanfu Huang, Kuo Li, Peiyuan Mei, Xiaojun Wang, Yongde Liao, Yunchong Meng\",\"doi\":\"10.1158/0008-5472.CAN-24-0249\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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. 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NUAK1-Mediated Phosphorylation of NADK Mitigates ROS Accumulation to Promote Osimertinib Resistance in Non-Small Cell Lung Carcinoma.
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.
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.