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Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model

Roque Diaz1, Paul A Nguewa1, Ricardo Parrondo2, Carlos Perez-Stable2, Irene Manrique1, Miriam Redrado1, Raul Catena1, Maria Collantes3, Ivan Peñuelas34, Juan Antonio Díaz-González4 and Alfonso Calvo1*

  • * Corresponding author: Alfonso Calvo

  • † Equal contributors

Author Affiliations

1 Division of Oncology, Center for Applied Medical Research (CIMA). University of Navarra, Pamplona, Spain

2 Geriatric Research, Education, and Clinical Center and Research Service, Veterans Affairs Medical Center; Department of Medicine and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami Florida 33125, USA

3 Small Animal Imaging Research Unit, Center for Applied Medical Research (CIMA) and Clínica Universidad de Navarra, Pamplona, Spain

4 Department of Oncology, Clínica Universidad de Navarra, Pamplona, Spain

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BMC Cancer 2010, 10:188  doi:10.1186/1471-2407-10-188

Published: 11 May 2010



There is strong evidence demonstrating that activation of epidermal growth factor receptors (EGFRs) leads to tumor growth, progression, invasion and metastasis. Erlotinib and gefitinib, two EGFR-targeted agents, have been shown to be relevant drugs for lung cancer treatment. Recent studies demonstrate that lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast cancer. In this report, we investigated the activity of lapatinib against non-small cell lung cancer (NSCLC).


We selected the lung cancer cell line A549, which harbors genomic amplification of EGFR and HER-2. Proliferation, cell cycle analysis, clonogenic assays, and signaling cascade analyses (by western blot) were performed in vitro. In vivo experiments with A549 cells xenotransplanted into nude mice treated with lapatinib (with or without radiotherapy) were also carried out.


Lapatinib dramatically reduced cell proliferation (P < 0.0001), DNA synthesis (P < 0.006), and colony formation capacity (P < 0.0001) in A549 cells in vitro. Furthermore, lapatinib induced G1 cell cycle arrest (P < 0.0001) and apoptotic cell death (P < 0.0006) and reduced cyclin A and B1 levels, which are regulators of S and G2/M cell cycle stages, respectively. Stimulation of apoptosis in lapatinib-treated A549 cells was correlated with increased cleaved PARP, active caspase-3, and proapoptotic Bak-1 levels, and reduction in the antiapoptic IAP-2 and Bcl-xL protein levels. We also demonstrate that lapatinib altered EGFR/HER-2 signaling pathways reducing p-EGFR, p-HER-2, p-ERK1/2, p-AKT, c-Myc and PCNA levels. In vivo experiments revealed that A549 tumor-bearing mice treated with lapatinib had significantly less active tumors (as assessed by PET analysis) (P < 0.04) and smaller in size than controls. In addition, tumors from lapatinib-treated mice showed a dramatic reduction in angiogenesis (P < 0.0001).


Overall, these data suggest that lapatinib may be a clinically useful agent for the treatment of lung cancer.