Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Nanchang University, No. 17 Yongwaizheng Street, Nanchang, 330006, Jiangxi, People's Republic of China.
Department of Healthy, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People's Republic of China.
Mol Cell Biochem. 2020 Dec;475(1-2):15-25. doi: 10.1007/s11010-020-03854-z. Epub 2020 Aug 6.
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.
在诊断为非小细胞肺癌 (NSCLC) 的患者中，约有 10%~30%观察到表皮生长因子受体 (EGFR) 基因的酪氨酸激酶 (TK) 结构域中的激活突变，并且与 NSCLC 的发生和进展有因果关系。针对 EGFR 的酪氨酸激酶抑制剂 (TKI) 的治疗显著改善了 EGFR 突变的 NSCLC 患者的预后，但常伴有耐药性，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 的激活与有丝分裂调节剂、有丝分裂期永不进入基因 A 相关激酶 2 (NEK2) 的上调高度相关。NEK2 的过表达与 EGFR 突变患者的不良生存相关，但与野生型患者无关。进一步的功能验证表明，EGFR 突变通过激活 ERK 信号通路诱导 NEK2 的表达。升高的 NEK2 水平促进 EGFR 突变型 NSCLC 细胞的快速细胞周期进程，并有利于其快速增殖。值得注意的是，NEK2 的过表达还通过抑制细胞凋亡来损害 TKI 治疗的疗效，而耗尽 NEK2 则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 突变调控的癌基因，参与 EGFR 突变的 NSCLC 疾病进展和治疗反应。这些发现将为优化个性化治疗策略以克服耐药性和改善 EGFR 突变肺癌患者的预后铺平道路。
