BEZ235 reduction of cisplatin resistance on wild-type EGFR non-small cell lung cancer cells
- J Chemother. 2022 Mar 3;1-9. doi: 10.1080/1120009X.2022.2045826.
- 1. Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Anhui Medical University, Hefei, China.
- 2. Pulmonary and Critical Care Medicine, First Affiliated Hospital, Anhui University of Science & Technology (Huainan First People's Hospital), Huainan, China.
- 3. Medical School, Anhui University of Science & Technology, Huainan, China.
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.