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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects*
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Drug Resistance, Neoplasm / drug effects
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ErbB Receptors / genetics*
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Gefitinib
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / genetics
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Lung Neoplasms / pathology*
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Mice
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Mice, Nude
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Mutation / genetics*
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Proto-Oncogene Proteins c-myc / metabolism
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Quinazolines / pharmacology*
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Treatment Outcome
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Up-Regulation / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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N-(2-bromo-5-(trifluoromethyl)phenyl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine
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PMAIP1 protein, human
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-myc
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Quinazolines
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ErbB Receptors
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Gefitinib
Grants and funding
This work was supported by the National Key Program for Basic Research (2012CB910800, 2010CB833200, 2010CB529201), the National Natural Science Foundation (No. 81071930, 81171925, 20972160 and 21172220), the Special Foundation of President and the Key Project of Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX1-YW-R-26 and KSCX2-YW-R-235), and the National Major Scientific and Technological Program for Drug Discovery (2009ZX09103-101). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.