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Article

Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation

  • Authors:
    • Geping Qu
    • Changting Liu
    • Baojun Sun
    • Changxi Zhou
    • Zhijian Zhang
    • Peng Wang
  • View Affiliations / Copyright

    Affiliations: Nanlou Respiratory Diseases Department, The Chinese People's Liberation Army (PLA) General Hospital, Beijing 100853, P.R. China
  • Pages: 341-347
    |
    Published online on: May 15, 2014
       https://doi.org/10.3892/or.2014.3178
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Abstract

Although the EGFR tyrosine kinase inhibitors (EGFR-TKI) erlotinib and gefitinib have shown marked effects against EGFR-mutated lung cancer, patients acquire resistance by various mechanisms, including the EGFR T790M mutation and Met induction, consequently suffering relapse. Thus, novel agents to overcome EGFR-TKI resistance are urgently needed. We aimed to investigate the inhibitory effects of a combination of BIBW2992 (irreversible EGFR inhibitor)/ARQ 197 (MET inhibitor) on the human lung adenocarcinoma cell line H1975. H1975 cells (harboring a T790M mutation in EGFR) were treated with erlotinib, BIBW2992 or ARQ 197 separately or with combinations of erlotinib/ARQ 197 or BIBW2992/ARQ 197. Cell growth, apoptosis and cell cycle distribution were evaluated by MTT assay, Annexin V/propidium iodide (PI) double staining and flow cytometry, respectively. EGFR, MET, AKT, ERK and the respective phosphorylated counterparts were detected by western blot analysis. Pathway-specific knockdown of MET and/or EGFR kinase signaling was achieved by siRNA interference. H1975 cells displayed EGFR and MET activation, and were resistant to erlotinib. The BIBW2992/ARQ 197 combination significantly inhibited growth, induced cell cycle arrest and apoptosis, and altered the phosphorylation of EGFR, MET, AKT and ERK1/2 in the H1975 cells. Phosphorylation of AKT and ERK1/2, downstream effectors of the EGFR and MET pathways, was not affected by the other tested treatments. Finally, knockdown of MET and/or EGFR in the H1975 cells confirmed the enhanced downstream inhibition of both MET and EGFR pathways. Combination of an irreversible EGFR inhibitor and MET inhibitor is effective in controlling H1975 cells with acquired resistance to erlotinib, by a mechanism involving the downregulation of PI3K/AKT and MEK/ERK signaling pathways.
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Copy and paste a formatted citation
Spandidos Publications style
Qu G, Liu C, Sun B, Zhou C, Zhang Z and Wang P: Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation. Oncol Rep 32: 341-347, 2014.
APA
Qu, G., Liu, C., Sun, B., Zhou, C., Zhang, Z., & Wang, P. (2014). Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation. Oncology Reports, 32, 341-347. https://doi.org/10.3892/or.2014.3178
MLA
Qu, G., Liu, C., Sun, B., Zhou, C., Zhang, Z., Wang, P."Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation". Oncology Reports 32.1 (2014): 341-347.
Chicago
Qu, G., Liu, C., Sun, B., Zhou, C., Zhang, Z., Wang, P."Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation". Oncology Reports 32, no. 1 (2014): 341-347. https://doi.org/10.3892/or.2014.3178
Copy and paste a formatted citation
x
Spandidos Publications style
Qu G, Liu C, Sun B, Zhou C, Zhang Z and Wang P: Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation. Oncol Rep 32: 341-347, 2014.
APA
Qu, G., Liu, C., Sun, B., Zhou, C., Zhang, Z., & Wang, P. (2014). Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation. Oncology Reports, 32, 341-347. https://doi.org/10.3892/or.2014.3178
MLA
Qu, G., Liu, C., Sun, B., Zhou, C., Zhang, Z., Wang, P."Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation". Oncology Reports 32.1 (2014): 341-347.
Chicago
Qu, G., Liu, C., Sun, B., Zhou, C., Zhang, Z., Wang, P."Combination of BIBW2992 and ARQ 197 is effective against erlotinib-resistant human lung cancer cells with the EGFR T790M mutation". Oncology Reports 32, no. 1 (2014): 341-347. https://doi.org/10.3892/or.2014.3178
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