BEZ235 reduction of cisplatin resistance on wild-type EGFR non-small cell lung cancer cells. (17th February 2023)

• Record Type: Journal Article
• Authors: Wang, Ruikai; Li, Amin; Liu, Jiachang; Fang, Ming; Zhu, Yan; Huang, Juan; Liu, Yinjie; Huo, Long; You, Qinghai
• Is Part Of: Journal of chemotherapy. Volume 35:Number 2(2023)
• Page Start: 95
• Page End: 103
• Publication Date: 2023-02-17
• Subjects: AKT/mTOR pathway -- ATM/ATR/DNA-PKcs -- BEZ235 -- cisplatin -- non-small cell lung cancer -- resistance; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; 615.58
• DOI: 10.1080/1120009X.2022.2045826
• Languages: English
• ISSNs: 1120-009X

Abstract

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.