Abstract
Treatment of non-small cell lung cancer (NSCLC) with drugs targeting the epidermal growth factor receptor (EGFR), e.g., gefitinib and erlotinib, will eventually fail because of the development of secondary mutations such as T790M in EGFR. Strategies to overcome this resistance are therefore an urgent need. In this study, we synthesized a dozen of novel gefitinib analogues and evaluated their effects on L858R/T790M-EGFR harboring NSCLC cells, and reported that one of these gefitinib mimetics, N-(2-bromo-5-(trifluoromethyl) phenyl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine (hereafter, V1801), triggered apoptosis of the NSCLC cells and overcame gefitinib-resistance in mice inoculated with NCI-H1975 cells. Though V1801 only moderately inhibited EGFR kinase activity, it markedly induced the expression of the BH3-only protein Noxa, and Noxa silencing significantly reduced V1801-induced apoptosis of NCI-H1975 cells. It is showed that V1801 interfered with the expression of the transcription factor c-Myc and the extracellular signal regulated kinase (Erk) pathway. V1801 in combination with proteasome inhibitor bortezomib exerted enhanced cytotoxicity in NCI-H1975 cells possibly due to potentiated induction of Noxa expression. These data indicate that gefinitib analogues with weak EGFR inhibitory activity may overcome drug-resistance via activation of BH-3 only pro-apoptotic proteins, and V1801 may have therapeutic potentials for NSCLC.
Highlights
Lung cancer is the one of the most frequent neoplasm worldwide, comprising 17% of the total new cancer cases and 23% of the total cancer deaths in males [1]
Using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, we showed that V1801 displayed significant inhibitory effects against the proliferation of NCI-H1975 (Fig. 1a) and wild type epidermal growth factor receptor (EGFR)-expressing A549 (Fig. 1b) cells in a dosedependent fashion
We design, synthesize and evaluated a number of novel quinazoline derivatives by exchanging the positions of the C5 and C6 substituents and varying the C4-amino functionality of gefitinib, and report that compound V1801 having a trifluoromethyl group at the C5’-position and a bromine at the C2’-position of the aniline moiety substituted at the C4 position of quinazoline core overcomes gefitinib resistance via up-regulation of Noxa, suggesting a novel strategy to fight against non-small cell lung cancer (NSCLC) with EGFR T790M mutation
Summary
Lung cancer is the one of the most frequent neoplasm worldwide, comprising 17% of the total new cancer cases and 23% of the total cancer deaths in males [1]. Treatment of lung cancer is determined by the histologic type and stage at diagnosis, and mainly includes surgery, platinum doublet therapy, radiation therapy and targeted therapy, with an only 15% of five-year overall survival rate for all stages combined [2]. The epidermal growth factor receptor (EGFR)-targeting agents including EGFRspecific antibodies and tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib, benefit a proportion of patients especially those never-smoke and of Asian origin [3,4,5]. Treatment with gefitinib and erlotinib will eventually fail because of the development of acquired drug resistance resulting from amplification of the MET proto-oncogene or the threonine-to-methionine amino acid substitution at position 790 (T790M) of EGFR, which is detected in 50% of clinically resistant patients [6,7]. Strategies to overcome EGFR TKI resistance remain practical needs in order to prolong survival time of patients with lung cancer
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