title: JAK2 inhibitor TG101348 overcomes erlotinib-resistance in non-small cell lung carcinoma cells with mutated EGF receptor.
abstract: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, NSCLC patients with secondary somatic EGFR mutations are resistant to EGFR-TKI treatment. In this study, we investigated the effect of TG101348 (a JAK2 inhibitor) on the tumor growth of erlotinib-resistant NSCLC cells. Cell proliferation, apoptosis, gene expression and tumor growth were evaluated by diphenyltetrazolium bromide (MTT) assay, flow cytometry, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, Western Blot and a xenograft mouse model, respectively. Results showed that erlotinib had a stronger impact on the induction of apoptosis in erlotinib-sensitive PC-9 cells but had a weaker effect on erlotinib-resistant H1975 and H1650 cells than TG101348. TG101348 significantly enhanced the cytotoxicity of erlotinib to erlotinib-resistant NSCLC cells, stimulated erlotinib-induced apoptosis and downregulated the expressions of EGFR, p-EGFR, p-STAT3, Bcl-xL and survivin in erlotinib-resistant NSCLC cells. Moreover, the combined treatment of TG101348 and erlotinib induced apoptosis, inhibited the activation of p-EGFR and p-STAT3, and inhibited tumor growth of erlotinib-resistant NSCLC cells in vivo. Our results indicate that TG101348 is a potential adjuvant for NSCLC patients during erlotinib treatment.
authors: Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors: Fu-quan
authors: FQ
authors: Zhang
authors: Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors: Wen-tao
authors: WT
authors: Yang
authors: Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors: Shan-zhou
authors: SZ
authors: Duan
authors: Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors: Ying-chen
authors: YC
authors: Xia
authors: Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors: Rong-ying
authors: RY
authors: Zhu
authors: Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
authors: Yong-bing
authors: YB
authors: Chen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005260:Female; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D011759:Pyrrolidines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D000096926:Benzenesulfonamides
chemical_list: D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D053614:Janus Kinase 2; D011759:Pyrrolidines; D013449:Sulfonamides; C528327:fedratinib; D000096926:Benzenesulfonamides; C512478:EGFR protein, human; C507924:JAK2 protein, human
keywords: TG101348; cancer therapy; drug resistance; erlotinib; non-small cell lung cancer