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Anticancer Original Research Papers

BEZ235 reduction of cisplatin resistance on wild-type EGFR non-small cell lung cancer cells

, , , , , , , & show all
Pages 95-103 | Received 14 Sep 2021, Accepted 20 Feb 2022, Published online: 03 Mar 2022
 

Abstract

Cisplatin, as a first-line chemotherapy drug for advanced wild-type epidermal growth factor receptor (wtEGFR) non-small cell lung cancer (NSCLC), often loses effectiveness because of acquired drug resistance. We found that ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) of DNA repair kinases and signal transduction molecules, protein kinase B (AKT)/target mammalian target of rapamycin (mTOR), were significantly phosphorylated in cisplatin-resistant wtEGFR NSCLC cell lines (H358R and A549R) than in their parental cells. Also, BEZ235 (dual phosphatidylinositol-3-kinase (PI3K)/mTOR inhibitor) significantly decreased the phosphorylation levels of these kinases/proteins, as detected by Western blot analysis. In H358R and A549R cells, the results of indirect immunofluorescence, single-cell gel electrophoresis, flow cytometry, methylthiazolyldiphenyl-tetrazolium bromide, clone formation assay, and scratch healing experiment showed that BEZ235 enhanced cisplatin-induced DNA damage and cell apoptosis, and effectively inhibited cellular proliferation/migration when combined with cisplatin. The data indicated that the abnormal activation of ATM/ATR/DNA-PKcs kinases and AKT/mTOR pathway might induce wtEGFR NSCLC cell resistance to cisplatin. The effects of the combination of BEZ235 and cisplatin suggested that BEZ235 should be considered as a combination therapy for patients with cisplatin-resistant wtEGFR NSCLC.

Disclosure statement

The authors have no conflicts of interest to declare.

Data availability statement

All data generated or analyzed during this study are included in this article.

Additional information

Funding

University Natural Science Research Project of Anhui Province (KJ2020A0338) funded this research.

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