JAK2 inhibitor TG101348 overcomes erlotinib-resistance in non-small cell lung carcinoma cells with mutated EGF receptor

// Fu-quan Zhang 1,* , Wen-tao Yang 1,* , Shan-zhou Duan 1 , Ying-chen Xia 1 , Rong-ying Zhu 1 and Yong-bing Chen 1 1 Department of Cardiothoracic Surgery, the Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China * These authors have contributed equally to this work Correspondence to: Yong-bing Chen, email: // Keywords : non-small cell lung cancer, TG101348, erlotinib, drug resistance, cancer therapy Received : November 14, 2014 Accepted : March 03, 2015 Published : March 29, 2015 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.