WZ4003 sensitizes non-small cell lung cancer cells to gefitinib via inhibition of ARK5 and epithelial-to-mesenchymal transition

Jiabin Chen; Shufen Zhang; Xiaoxiao Zheng; Jiayan Mao; Shangzhi Xie; Wei Chen; Xiangui Ran

WZ4003 sensitizes non-small cell lung cancer cells to gefitinib via inhibition of ARK5 and epithelial-to-mesenchymal transition

Am J Transl Res. 2020 Nov 15;12(11):7377-7385. eCollection 2020.

Authors

Jiabin Chen^{1

2}, Shufen Zhang^{1

2}, Xiaoxiao Zheng^{1

2}, Jiayan Mao^{1

2}, Shangzhi Xie^{1

2}, Wei Chen^{1

2}, Xiangui Ran³

Affiliations

¹ Cancer Institute of Integrated Traditional Chinese and Western Medicine, Zhejiang Academy of Traditional Chinese Medicine, Tongde Hospital of Zhejiang Province Hangzhou 310012, Zhejiang, China.
² Department of Medical Oncology, Tongde Hospital of Zhejiang Province Hangzhou 310012, Zhejiang, China.
³ Department of Respiratory, Fuyang People's Hospital No. 63, Lushi Street, Fuyang 236000, Anhui, China.

PMID: 33312374
PMCID: PMC7724321

Abstract

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, is used as a first-line treatment for advanced non-small cell lung cancer (NSCLC); however, its utility is hampered by the development of chemoresistance. This study aimed to investigate the synergistic role of WZ4003, a novel (nua) kinase (NUAK) inhibitor, in enhancing gefitinib sensitivity in NSCLC cells. Our data indicated WZ4003 enhances the sensitivity of NSCLC cells to gefitinib. We also found ARK5 knockdown in NSCLC cell lines increased their sensitivity to gefitinib. However, WZ4003 did not affect gefitinib sensitivity when ARK5 was knocked down in NSCLC cell lines (using siRNA). Both WZ4003 and ARK5 inhibition suppressed epithelial-to-mesenchymal transition by reducing the expression of vimentin and increasing E-cadherin expression. Together, our results demonstrate WZ4003 plays a vital role in releasing acquired resistance to gefitinib by inhibiting ARK5 and epithelial-to-mesenchymal transition. Therefore, synergistic use of WZ4003 and gefitinib may prevent the development of gefitinib resistance in NSCLC.

Keywords: Non-small cell lung cancer (NSCLC); WZ4003; epithelial to mesenchymal transition (EMT); gefitinib.