Activating mutations within the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR) gene are observed in 10 ~ 30% of the patients diagnosed with non-small cell lung cancer (NSCLC), and are causally related to NSCLC initiation and progression. Treatments with tyrosine kinase inhibitors (TKIs) targeting EGFR significantly improve the outcome of NSCLC patients with EGFR mutation, but are often associated with drug resistance, which is the main cause of treatment failure and cancer relapse. In the present study, by screening the transcriptome of NSCLC patients, we found that EGFR activation is highly correlated with the up-regulation of mitotic regulator, never in mitosis gene A-related kinase 2 (NEK2). NEK2 overexpression is associated with the poor survival of EGFR-mutant patients but not the wild-type patients. Further functional validation revealed that EGFR mutation induces NEK2 expression by activating ERK signaling pathway. Elevated NEK2 level promotes the rapid cell cycle progression and favors the rapid proliferation of EGFR-mutant NSCLC cells. Of note, NEK2 overexpression also impairs the efficacy of TKI treatment via inhibiting apoptosis, while depleting NEK2 suppresses cell growth and restored the sensitivity of TKI in NSCLC cells. Taken together, our study revealed that NEK2 is an oncogene regulated by EGFR mutation and is involved in disease progression and treatment response in NSCLC with EGFR mutation. These findings will pave the road for optimizing personalized treatment strategies to overcome drug resistance and improve the prognosis of lung cancer patients with EGFR mutation.

在表皮生长因子受体（EGFR）基因的酪氨酸激酶（TK）域内的激活突变在诊断为非小细胞肺癌（NSCLC）的患者中有10〜30％观察到，并且与NSCLC的发生和发展有因果关系。用靶向EGFR的酪氨酸激酶抑制剂（TKIs）治疗可显着改善EGFR突变的NSCLC患者的预后，但通常与耐药性相关，这是治疗失败和癌症复发的主要原因。在本研究中，通过筛选NSCLC患者的转录组，我们发现EGFR激活与有丝分裂调节剂的上调高度相关，而在有丝分裂基因A相关激酶2（NEK2）中则从未如此。NEK2过表达与EGFR突变患者的不良存活有关，而与野生型患者无关。进一步的功能验证表明，EGFR突变通过激活ERK信号传导途径诱导NEK2表达。升高的NEK2水平促进细胞周期的快速发展，并促进EGFR突变的NSCLC细胞的快速增殖。值得注意的是，NEK2的过表达还通过抑制细胞凋亡来削弱TKI治疗的功效，而消耗NEK2则可以抑制细胞生长并恢复NSCLC细胞中TKI的敏感性。综上所述，我们的研究表明NEK2是受EGFR突变调控的致癌基因，并参与具有EGFR突变的NSCLC的疾病进展和治疗反应。这些发现将为优化个性化治疗策略铺平道路，以克服耐药性并改善具有EGFR突变的肺癌患者的预后。