title: Continuous exposure of non-small cell lung cancer cells with wild-type EGFR to an inhibitor of EGFR tyrosine kinase induces chemoresistance by activating STAT3.
abstract: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR‑TKIs) have shown promising effects against the growth of non-small cell lung cancer (NSCLC) cells harboring EGFR mutations (EGFR‑mts). However, many patients with NSCLC that are accepted for EGFR‑TKI treatment followed by chemotherapy possess an unknown EGFR status including wild-type EGFR (EGFR‑wt). Little is known about the potential effects of EGFR‑TKI treatment prior to chemotherapy. We investigated the effects and underlying molecular events of 4 weeks of continuous exposure to EGFR‑TKIs in the EGFR‑wt NSCLC line H1299. This treatment dramatically increased the IC50 of several relevant chemotherapeutic agents: cisplatin (DDP) (29.25±6.1 µM for gefitinib, 43.25±14.87 µM for erlotinib, and 6.92±1.15 µM for parental), paclitaxel (11.16±3.36 µM for gefitinib, 9.16±1.41 µM for erlotinib, and 2.09±0.44 µM for parental), gemcitabine (47.18±6.2 µM for gefitinib, 40.36±11.1 µM for erlotinib, and 16.00±3.38 µM for parental) and pemetrexed (11.78±4.07 µM for gefitinib, 15.97±7.23 µM for erlotinib, and 4.72±1.9 µM for parental). This chemoresistance was critically dependent on the activation of the mediator signal transducer and activator of transcription 3 (STAT3). In cells exposed to EGFR‑TKIs for 4 weeks, activation of STAT3 was found to be unrelated to EGFR and to be independent of IL‑6 and ‑22. Treatment with the STAT3 inhibitor NSC 74859 was able to reverse the TKI exposure-induced chemoresistance in EGFR‑wt NSCLC cells. Similar phenomena were observed in H1975 cells harboring EGFR L858R and T790M mutations. Based on the observed molecular events following long exposure of an EGFR‑wt NSCLC cell line to an EGFR‑TKI, this study indicates that such drugs should be not recommended for EGFR‑wt patients who can undergo chemotherapy. This study also suggests that STAT3 inhibitors may aid in the treatment NSCLC patients who exhibit EGFR‑TKI resistance due to an acquired T790M mutation.
authors.affiliation: Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospita, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospita, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Fuchun
authors.initials: F
authors.lastname: Guo
authors.affiliation: Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospita, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Du
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospita, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospita, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Qin
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospita, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yin
authors.affiliation: Department of Abdominal Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospita, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.affiliation: Department of Thoracic Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospita, Chengdu, Sichuan 610041, P.R. China.
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D018773:Genes, erbB-1; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors