Lin Wei, Wang Na, Wu Shihao, Diao Mingxin, Huang Quanfu, Li Kuo, Mei Peiyuan, Wang Xiaojun, Liao Yongde, Meng Yunchong
Department of Thoracic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Thoracic Surgery, Fujian Medical University Union Hospital, Fuzhou, China.
Cancer Res. 2024 Dec 2;84(23):4081-4098. doi: 10.1158/0008-5472.CAN-24-0249.
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.
奥希替尼是一种第三代表皮生长因子受体酪氨酸激酶抑制剂，被批准用于治疗具有表皮生长因子受体（EGFR）激活突变或T790M耐药突变的晚期非小细胞肺癌（NSCLC）患者的一线治疗。然而，由于获得性耐药，奥希替尼的疗效受到限制，这凸显了阐明耐药机制以促进改进治疗策略发展的必要性。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显著上调基因，并确定NUAK1是奥希替尼耐药的关键调节因子。NUAK1在奥希替尼耐药的NSCLC中高表达，并促进奥希替尼耐药的出现。对NUAK1进行基因或药理学阻断可在体外和体内恢复耐药NSCLC细胞对奥希替尼的敏感性。从机制上讲，NUAK1直接与烟酰胺腺嘌呤二核苷酸激酶（NADK）相互作用，并在丝氨酸64（S64）位点使其磷酸化，这减轻了奥希替尼诱导的活性氧（ROS）积累，并导致NSCLC获得奥希替尼耐药性。此外，虚拟药物筛选确定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积累来逆转获得性耐药。总的来说，这些发现突出了NUAK1-NADK轴在NSCLC奥希替尼耐药中的作用，并表明靶向该轴作为规避耐药的策略具有潜力。意义：NUAK1对NADK的磷酸化减少了ROS积累，并赋予对奥希替尼的耐药性，确定NUAK1-NADK信号通路是改善肺癌对EGFR抑制反应的潜在治疗靶点。
