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High expression of NEK2 promotes lung cancer progression and drug resistance and is regulated by mutant EGFR

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Abstract

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.

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Author notes

  1. Chuanhui Chen and Shanshan Peng have contribute equally to this work.

Authors and Affiliations

  1. 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

    Chuanhui Chen, Penghui Li, Lin Ma & Xin Gan

  2. Department of Healthy, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China

    Shanshan Peng

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  1. Chuanhui Chen
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Correspondence to Xin Gan.

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Chen, C., Peng, S., Li, P. et al. High expression of NEK2 promotes lung cancer progression and drug resistance and is regulated by mutant EGFR. Mol Cell Biochem 475, 15–25 (2020). https://doi.org/10.1007/s11010-020-03854-z

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