Silencing Nrf2 in cisplatin resistant non-small cell lung cancer cells augments sensitivity towards EGFR inhibitor

• Published in: Toxicology in vitro 2024-12, Vol.101, p.105921, Article 105921
• Main Authors: Fouzder, Chandrani, Mukhuty, Alpana, Chattopadhyay, Dipanjan, Das, Snehasis, Hira, Sumit Kumar, Kundu, Rakesh
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cisplatin - pharmacology; Cisplatin resistance; Drug Resistance, Neoplasm - drug effects; EGFR; EGFR inhibitor; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gene Silencing; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; NSCLC; Quinazolines - pharmacology; Tyrphostins - pharmacology
• ISSN: 0887-2333; 1879-3177; 1879-3177
• DOI: 10.1016/j.tiv.2024.105921

Recently, non-small cell lung cancer (NSCLC) has been the prime concern of cancer clinicians due to its high mortality rate worldwide. Cisplatin, a platinum derivative, has been used as a therapeutic option for treating metastatic NSCLC for several years. However, acquired, or intrinsic drug resistance to Cisplatin is the major obstacle to the successful treatment outcome of patients. Dysregulation of Nrf2 (nuclear factor erythroid 2-related factor 2) and EGFR (epidermal growth factor receptor) signaling have been associated with cellular proliferation, cancer initiation, progression and confer drug resistance to several therapeutic agents including Cisplatin in various cancers. To dissect the molecular mechanism of EGFR activation in resistant cells, we developed Cisplatin-resistant (CisR) human NSCLC cell lines (A549 and NCIH460) with increasing doses of Cisplatin treatment over a 3-month period. CisR cells demonstrated increased proliferative capacity, clonogenic survivability and drug efflux activity compared to the untreated parental (PT) cells. These resistant cells also showed higher levels of Nrf2 and EGFR expression. Here, we found that Nrf2 upregulates both basal and inducible expression of EGFR in these CisR cells at the transcriptional level. Moreover, genetic inhibition of Nrf2 with siRNA in CisR cells showed increased sensitivity towards the EGFR tyrosine kinase inhibitor (TKIs), AG1478. Our study, therefore suggests the use of Nrf2 inhibitors in combinatorial therapy with EGFR TKIs for the treatment of resistant NSCLC. •Cisplatin-resistant NSCLC cells (CisR) were developed over a 3-month period.•CisR cells showed high Nrf2 and EGFR levels that conferred drug resistance.•Nrf2 regulates the expression of EGFR in resistant cell types.•Silencing Nrf2 downregulates EGFR and improves sensitivity to EGFR inhibitors.