Identifying Differentially Expressed Genes and Screening Small Molecule Drugs for Lapatinib-resistance of Breast Cancer by a Bioinformatics Strategy

  • Zhuo, Wen-Lei (Institute of Cancer, Xinqiao Hospital, Third Military Medical University) ;
  • Zhang, Liang (Institute of Cancer, Xinqiao Hospital, Third Military Medical University) ;
  • Xie, Qi-Chao (Institute of Cancer, Xinqiao Hospital, Third Military Medical University) ;
  • Zhu, Bo (Institute of Cancer, Xinqiao Hospital, Third Military Medical University) ;
  • Chen, Zheng-Tang (Institute of Cancer, Xinqiao Hospital, Third Military Medical University)
  • 발행 : 2015.01.22


Background: Lapatinib, a dual tyrosine kinase inhibitor that interrupts the epidermal growth factor receptor (EGFR) and HER2/neu pathways, has been indicated to have significant efficacy in treating HER2-positive breast cancer. However, acquired drug resistance has become a very serious clinical problem that hampers the use of this agent. In this study, we aimed to screen small molecule drugs that might reverse lapatinib-resistance of breast cancer by exploring differentially expressed genes (DEGs) via a bioinformatics method. Materials and Methods: We downloaded the gene expression profile of BT474-J4 (acquired lapatinib-resistant) and BT474 (lapatinib-sensitive) cell lines from the Gene Expression Omnibus (GEO) database and selected differentially expressed genes (DEGs) using dChip software. Then, gene ontology and pathway enrichment analyses were performed with the DAVID database. Finally, a connectivity map was utilized for predicting potential chemicals that reverse lapatinib-resistance. Results: A total of 1, 657 DEGs were obtained. These DEGs were enriched in 10 pathways, including cell cycling, regulation of actin cytoskeleton and focal adhesion associate examples. In addition, several small molecules were screened as the potential therapeutic agents capable of overcoming lapatinib-resistance. Conclusions: The results of our analysis provided a novel strategy for investigating the mechanism of lapatinib-resistance and identifying potential small molecule drugs for breast cancer treatment.


  1. Andl CD (2010). The Misregulation of Cell Adhesion Components during Tumorigenesis: Overview and Commentary. J Oncol, 2010, 174715.
  2. Ba JL, Liu CG, Jin F (2014). Alterations in hormonal receptor expression and HER2 status between primary breast tumors and paired nodal metastases: discordance rates and prognosis. Asian Pac J Cancer Prev, 15, 9233-9.
  3. Bailey ST, Miron PL, Choi YJ, et al (2014). NF-kappaB activation-induced anti-apoptosis renders HER2-positive cells drug resistant and accelerates tumor growth. Mol Cancer Res, 12, 408-20.
  4. Brady SW, Zhang J, Seok D, et al (2014). Enhanced PI3K p110alpha signaling confers acquired lapatinib resistance that can be effectively reversed by a p110alpha-selective PI3K inhibitor. Mol Cancer Ther, 13, 60-70.
  5. Chang WT, Cheng HL, Hsieh BS, et al (2014). Progesterone increases apoptosis and inversely decreases autophagy in human hepatoma HA22T/VGH cells treated with epirubicin. Scientific World J, 2014, 567148.
  6. Chen HY, Chen XY (2013). Tetrandrine reversed the resistance of tamoxifen in human breast cancer MCF-7/TAM cells: an experimental research. Zhongguo Zhong Xi Yi Jie He Za Zhi, 33, 488-91.
  7. Cufi S, Vazquez-Martin A, Oliveras-Ferraros C, et al (2013). The anti-malarial chloroquine overcomes primary resistance and restores sensitivity to trastuzumab in HER2-positive breast cancer. Sci Rep, 3, 2469.
  8. De Luca A, D'Alessio A, Gallo M, et al (2014). Src and CXCR4 are involved in the invasiveness of breast cancer cells with acquired resistance to lapatinib. Cell Cycle, 13, 148-56.
  9. Eke I, Cordes N (2014). Focal adhesion signaling and therapy resistance in cancer. Semin Cancer Biol.
  10. Eljack ND, Ma HY, Drucker J, et al (2014). Mechanisms of cell uptake and toxicity of the anticancer drug cisplatin. Metallomics, 6, 2126-33.
  11. Formisano L, Nappi L, Rosa R, et al (2014). Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models. Breast Cancer Res, 16, 45.
  12. Froidevaux-Klipfel L, Poirier F, Boursier C, et al (2011). Modulation of septin and molecular motor recruitment in the microtubule environment of the Taxol-resistant human breast cancer cell line MDA-MB-231. Proteomics, 11, 3877-86.
  13. Gao JL, Ji X, He TC, et al (2013). Tetrandrine suppresses cancer angiogenesis and metastasis in 4T1 tumor bearing mice. Evid Based Complement Alternat Med, 2013, 265061.
  14. Hardy KD, Wahlin MD, Papageorgiou I, et al (2014). Studies on the role of metabolic activation in tyrosine kinase inhibitor-dependent hepatotoxicity: induction of CYP3A4 enhances the cytotoxicity of lapatinib in HepaRG cells. Drug Metab Dispos, 42, 162-71.
  15. Howe EN, Cochrane DR, Cittelly DM, et al (2012). miR-200c targets a NF-kappaB up-regulated TrkB/NTF3 autocrine signaling loop to enhance anoikis sensitivity in triple negative breast cancer. PLoS One, 7, 49987.
  16. Huang YH, Zhang SH, Zhen RX, et al (2004). Asiaticoside inducing apoptosis of tumor cells and enhancing anti-tumor activity of vincristine. Ai Zheng, 23, 1599-604.
  17. Janji B, Vallar L, Al Tanoury Z, et al (2010). The actin filament cross-linker L-plastin confers resistance to TNF-alpha in MCF-7 breast cancer cells in a phosphorylation-dependent manner. J Cell Mol Med, 14, 1264-75.
  18. Kacan T, Altun A, Altun GG, et al (2014). Investigation of antitumor effects of sorafenib and lapatinib alone and in combination on MCF-7 breast cancer cells. Asian Pac J Cancer Prev, 15, 3185-9.
  19. Kim HP, Han SW, Song SH, et al (2014). Testican-1-mediated epithelial-mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer. Oncogene, 33, 3334-41.
  20. Kumar S, Park SH, Cieply B, et al (2011). A pathway for the control of anoikis sensitivity by E-cadherin and epithelial-to-mesenchymal transition. Mol Cell Biol, 31, 4036-51.
  21. Lamb J, Crawford ED, Peck D, et al (2006). The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science, 313, 1929-35.
  22. Li J, Cho YY, Langfald A, et al (2011). Lapatinib, a preventive/therapeutic agent against mammary cancer, suppresses RTK-mediated signaling through multiple signaling pathways. Cancer Prev Res (Phila), 4, 1190-7.
  23. Li Z, Tian T, Hu X, et al (2013a). Six1 mediates resistance to paclitaxel in breast cancer cells. Biochem Biophys Res Commun, 441, 538-43.
  24. Li Z, Tian T, Lv F, et al (2013b). Six1 promotes proliferation of pancreatic cancer cells via upregulation of cyclin D1 expression. PLoS One, 8, 59203.
  25. Liu L, Greger J, Shi H, et al (2009). Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL. Cancer Res, 69, 6871-8.
  26. Liu Y, Ge J, Li Q, et al (2013). Anisomycin induces apoptosis of glucocorticoid resistant acute lymphoblastic leukemia CEM-C1 cells via activation of mitogen-activated protein kinases p38 and JNK. Neoplasma, 60, 101-10.
  27. McDermott MS, Browne BC, Conlon NT, et al (2014). PP2A inhibition overcomes acquired resistance to HER2 targeted therapy. Mol Cancer, 13, 157.
  28. Mithraprabhu S, Khong T, Spencer A (2014). Overcoming inherent resistance to histone deacetylase inhibitors in multiple myeloma cells by targeting pathways integral to the actin cytoskeleton. Cell Death Dis, 5, 1134.
  29. Ramsay EE, Dilda PJ (2014). Glutathione S-conjugates as prodrugs to target drug-resistant tumors. Front Pharmacol, 5, 181.
  30. SA VONS-H, Schmeel LC, Schmeel FC, et al (2014). Targeting the Wnt/beta-catenin pathway in renal cell carcinoma. Anticancer Res, 34, 4101-8.
  31. Schroeder RL, Stevens CL, Sridhar J (2014). Small molecule tyrosine kinase inhibitors of ErbB2/HER2/Neu in the treatment of aggressive breast cancer. Molecules, 19, 15196-212.
  32. Tang L, Wang Y, Strom A, et al (2013). Lapatinib induces p27 (Kip1)-dependent G (1) arrest through both transcriptional and post-translational mechanisms. Cell Cycle, 12, 2665-74.
  33. Truman JP, Garcia-Barros M, Obeid LM, et al (2014). Evolving concepts in cancer therapy through targeting sphingolipid metabolism. Biochim Biophys Acta, 1841, 1174-88.
  34. Ueki N, Lee S, Sampson NS, et al (2013). Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease. Nat Commun, 4, 2735.
  35. Wang P, Yuan HH, Zhang X, et al (2014). Novel lycorine derivatives as anticancer agents: synthesis and in vitro biological evaluation. Molecules, 19, 2469-80.
  36. Wang Q, Quan H, Zhao J, et al (2013). RON confers lapatinib resistance in HER2-positive breast cancer cells. Cancer Lett, 340, 43-50.
  37. Wilson AJ, Liu AY, Roland J, et al (2013). TR3 modulates platinum resistance in ovarian cancer. Cancer Res, 73, 4758-69.
  38. Xu CY, Jiang ZN, Zhou Y, et al (2013). Estrogen receptor alpha roles in breast cancer chemoresistance. Asian Pac J Cancer Prev, 14, 4049-52.
  39. Zhang Z, Wang J, Ji D, et al (2014). Functional genetic approach identifies MET, HER3, IGF1R, INSR pathways as determinants of lapatinib unresponsiveness in HER2-positive gastric cancer. Clin Cancer Res, 20, 4559-73.
  40. Zhao Q, Wu CZ, Lee JK, et al (2014). Anticancer effects of the Hsp90 inhibitor 17-demethoxy-reblastatin in human breast cancer MDA-MB-231 cells. J Microbiol Biotechnol, 24, 914-20.
  41. Zhou H, Shen T, Shang C, et al (2014). Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway. Oncotarget, 5, 10140-50.

피인용 문헌

  1. Identification of Biomarkers for Breast Cancer Using Databases vol.21, pp.4, 2016,