Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is approved as a first-line therapy in advanced non-small cell lung carcinoma (NSCLC) patients 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 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.

中文翻译：

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NUAK1 介导的 NADK 磷酸化可减轻 ROS 积累，从而促进非小细胞肺癌的奥希替尼耐药


奥希替尼是第三代表皮生长因子受体酪氨酸激酶抑制剂，被批准作为具有 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开发改进治疗策略的必要性。在这里，我们筛选了奥希替尼耐药 NSCLC 细胞中编码蛋白激酶的基因显著上调，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，并促进了奥希替尼耐药的出现。NUAK1 的遗传或药理学阻断在体外和体内恢复了耐药 NSCLC 细胞对奥希替尼的敏感性。从机制上讲，NUAK1 直接与丝氨酸 64 （S64） 位点的 NADK 相互作用并磷酸化，这减轻了奥希替尼诱导的活性氧 （ROS） 积累，并有助于在 NSCLC 中获得奥希替尼耐药。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 积累来逆转获得性耐药。总的来说，这些发现强调了 NUAK1-NADK 轴在控制 NSCLC 中奥希替尼耐药的作用，并表明将该轴作为规避耐药策略的潜力。