title: Fulvestrant increases gefitinib sensitivity in non-small cell lung cancer cells by upregulating let-7c expression.
abstract: Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), namely, gefitinib and erlotinib. However, these patients eventually develop resistance to EGFR-TKIs. About 50% of this acquired resistance may be the result of a secondary mutation in the EGFR gene, such as the one corresponding to T790M. In our previous study, we found that combined treatment with fulvestrant and gefitinib decreases the proliferation of H1975 NSCLC cells, compared to treatment with either fulvestrant or gefitinib alone; however, the molecular mechanism for the improved effects of the combination treatment are still unknown. In this study, we confirmed that fulvestrant increases the gefitinib sensitivity of H1975 cells and found that let-7c was most upregulated in the fulvestrant-treated cells. Our data revealed that let-7c increases gefitinib sensitivity by repressing RAS and inactivating the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways. Taken together, our findings suggest that let-7c plays an important role in fulvestrant-induced upregulation of gefitinib sensitivity in H1975 cells.
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Shen
authors.affiliation: Department of Cardiothoracic Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Jinyuan
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Pathology, Cancer Center, Nanjing Medical University, 210029 Nanjing, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Qian
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Ruitong
authors.initials: R
authors.lastname: Xu
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Tongpeng
authors.initials: T
authors.lastname: Xu
authors.affiliation: Department of Pathology, Cancer Center, Nanjing Medical University, 210029 Nanjing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Pathology, Cancer Center, Nanjing Medical University, 210029 Nanjing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Pathology, Cancer Center, Nanjing Medical University, 210029 Nanjing, China.
authors.forename: Zhumei
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Pathology, Cancer Center, Nanjing Medical University, 210029 Nanjing, China.
authors.forename: Jitai
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Pathology, Cancer Center, Nanjing Medical University, 210029 Nanjing, China.
authors.forename: Qiudan
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. Electronic address: shuyongqian@csco.org.cn.
authors.forename: Yongqian
authors.initials: Y
authors.lastname: Shu
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077267:Fulvestrant; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D011799:Quinazolines / Q000494:pharmacology*; D014162:Transfection; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D035683:MicroRNAs; D011799:Quinazolines; C487931:mirnlet7 microRNA, human; D000077267:Fulvestrant; D004958:Estradiol; D000077156:Gefitinib
keywords: Epidermal growth factor receptor; Fulvestrant; Gefitinib; Non-small cell lung cancer; Resistance