Gefitinib sensitization of cisplatin-resistant wild-type EGFR non-small cell lung cancer cells

Abstract

Purpose The usual first-line strategy of wild-type EGFR (wtEGFR) non-small cell lung cancer (NSCLC) remains cisplatinbased chemotherapy. However, cisplatin often loses effectiveness because most tumors acquire drug resistance over time. As EGFR is the most important pro-survival/proliferation signal receptor in NSCLC cells, we aimed at investigating whether cisplatin resistance is related to EGFR activation and further evaluating the combined effects of cisplatin/gefitinib (EGFRtyrosine kinase inhibitor, EGFR-TKI) on cisplatin-resistant wtEGFR NSCLC cells. Materials and methods EGFR activation was analysed in parental and cisplatin-resistant wtEGFR NSCLC cell lines (H358 and H358 R , A549 and A549 R ). Cellular proliferation and apoptosis of H358 R /A549 R cells treated with cisplatin or gefitinib, alone or in combination were investigated, and the related effector protein was detected by western blot analysis. Anti-tumor effect of two drugs combined was evaluated in animal models of H358 R xenografts in vivo. Results EGFR was significantly phosphorylated in cisplatin-resistant wtEGFR NSCLC cells H358 R and A549 R than their parental cells. In H358 R and A549 R cells, anti-proliferative ability of gefitinib was further improved, and gefitinib combined with cisplatin enhanced inhibition of cellular survive/proliferation, and promotion of apoptosis in vitro. The combined effects were also associated with the inhibition of EGFR downstream effector proteins. Similarly, in vivo, gefitinib and cisplatin in combination significantly inhibited tumor growth of H358 R xenografts. Conclusion Abnormal activation of EGFR may induce wtEGFR NSCLC cell resistance to cisplatin. The combined effects of cisplatin/gefitinib suggest that gefitinib, as a combination therapy for patients with cisplatin-resistant wtEGFR NSCLC should be considered.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Effect of Gefitinib Combined with Chemotherapy in Patients with Advanced NSCLC: A Retrospective Cohort Study

“…Gefitinib, an important EGFR-TKI inhibitor, can significantly inhibit tumor proliferation and growth by inhibiting EGFR tyrosine kinase activity and can promote tumor cell apoptosis. 20 A study 21 has shown that gefitinib can effectively inhibit a variety of tumor cell lines xenografted in nude mice and can also improve the antitumor effects of chemotherapy and radiotherapy. The clinical study of He et al 22 showed that these patients were significantly and effectively treated with gefitinib, and the disease-related symptoms were significantly improved, which improves the quality of life.…”

Synergistic cytotoxicity of the CDK4 inhibitor Fascaplysin in combination with EGFR inhibitor Afatinib against Non-small Cell Lung Cancer

“…In detail, cisplatin treatment followed by afatinib exposure showed higher activity against two EGFR wildtype HNSCC cell lines compared to other approaches. Furthermore, EGFR was found hyperphosphorylated in cisplatin-resistant wildtype EGFR NSCLC cells, H358 R and A549 R , and the cisplatin/ gefitinib combination applied promoted apoptotic cell death [28]. Another study employing five human EGFR wild-type HNSCC cell lines showed significant synergy of afatinib with cisplatin [29].…”

Brain‐specific serine/threonine‐protein kinase 1 is a substrate of protein kinase C epsilon involved in sex‐specific ethanol and anxiety phenotypes

“…[50][51][52][53][54][55][56][57][58] Why female Brsk1 À/À mice drink less is unclear but there is a growing literature on BRSK1's involvement in ovarian function, age of menopause onset, cervical cancer, and breast cancer. [59][60][61][62][63] Future work is needed to reveal the functional mechanisms involving BRSK1 that regulate ethanol drinking in females.…”

“…Notably, women with alcohol use disorder are at higher risk for negative health outcomes compared with men who consume comparable levels of alcohol 50–58 . Why female Brsk1 −/− mice drink less is unclear but there is a growing literature on BRSK1's involvement in ovarian function, age of menopause onset, cervical cancer, and breast cancer 59–63 . Future work is needed to reveal the functional mechanisms involving BRSK1 that regulate ethanol drinking in females.…”