Identifying differentially expressed genes and screening small molecule drugs for lapatinib-resistance of breast cancer by a bioinformatics strategy.

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.

• Publication year

  2015

• Venue

  Asian Pacific Journal of Cancer Prevention

• Publication date

  2015-01-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.7314/APJCP.2014.15.24.10847PMID 25605188
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Focal adhesion signaling and therapy resistance in cancer.

  2015cited by this paper
• Testican-1-mediated epithelial–mesenchymal transition signaling confers acquired resistance to lapatinib in HER2-positive gastric cancer

  2014cited by this paper
• Ciclopirox induces autophagy through reactive oxygen species-mediated activation of JNK signaling pathway

  2014cited by this paper
• Small Molecule Tyrosine Kinase Inhibitors of ErbB2/HER2/Neu in the Treatment of Aggressive Breast Cancer

  2014cited by this paper
• Overcoming inherent resistance to histone deacetylase inhibitors in multiple myeloma cells by targeting pathways integral to the actin cytoskeleton

  2014cited by this paper
• Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models

  2014cited by this paper
• Studies on the Role of Metabolic Activation in Tyrosine Kinase Inhibitor–Dependent Hepatotoxicity: Induction of CYP3A4 Enhances the Cytotoxicity of Lapatinib in HepaRG Cells

  2014cited by this paper
• Mechanisms of cell uptake and toxicity of the anticancer drug cisplatin.

  2014cited by this paper
• Progesterone Increases Apoptosis and Inversely Decreases Autophagy in Human Hepatoma HA22T/VGH Cells Treated with Epirubicin

  2014cited by this paper
• Glutathione S-conjugates as prodrugs to target drug-resistant tumors

  2014cited by this paper
• PP2A inhibition overcomes acquired resistance to HER2 targeted therapy

  2014cited by this paper
• Novel Lycorine Derivatives as Anticancer Agents: Synthesis and In Vitro Biological Evaluation

  2014cited by this paper
• Investigation of antitumor effects of sorafenib and lapatinib alone and in combination on MCF-7 breast cancer cells.

  2014cited by this paper
• Functional Genetic Approach Identifies MET, HER3, IGF1R, INSR Pathways as Determinants of Lapatinib Unresponsiveness in HER2-Positive Gastric Cancer

  2014cited by this paper
• Targeting the Wnt/beta-catenin pathway in renal cell carcinoma.

  2014cited by this paper
• Multidetector CT Improving Surgical Outcomes in Breast Cancer (MISO BC)

  2014cited by this paper
• Alterations in hormonal receptor expression and HER2 status between primary breast tumors and paired nodal metastases: discordance rates and prognosis.

  2014cited by this paper
• Anticancer effects of the Hsp90 inhibitor 17-demethoxy-reblastatin in human breast cancer MDA-MB-231 cells.

  2014cited by this paper
• Evolving concepts in cancer therapy through targeting sphingolipid metabolism.

  2014cited by this paper
• Src and CXCR4 are involved in the invasiveness of breast cancer cells with acquired resistance to lapatinib

  2014cited by this paper
• Six1 Promotes Proliferation of Pancreatic Cancer Cells via Upregulation of Cyclin D1 Expression

  2013cited by this paper
• Estrogen receptor α roles in breast cancer chemoresistance.

  2013cited by this paper
• Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease

  2013cited by this paper
• RON confers lapatinib resistance in HER2-positive breast cancer cells.

  2013cited by this paper
• TR3 modulates platinum resistance in ovarian cancer.

  2013cited by this paper
• Tetrandrine Suppresses Cancer Angiogenesis and Metastasis in 4T1 Tumor Bearing Mice

  2013cited by this paper
• Six1 mediates resistance to paclitaxel in breast cancer cells.

  2013cited by this paper
• [Tetrandrine reversed the resistance of tamoxifen in human breast cancer MCF-7/TAM cells: an experimental research].

  2013cited by this paper
• Enhanced PI3K p110α Signaling Confers Acquired Lapatinib Resistance That Can Be Effectively Reversed by a p110α-Selective PI3K Inhibitor

  2013cited by this paper
• The anti-malarial chloroquine overcomes Primary resistance and restores sensitivity to Trastuzumab in HER2-positive breast cancer

  2013cited by this paper
• NF-κB Activation-Induced Anti-apoptosis Renders HER2-Positive Cells Drug Resistant and Accelerates Tumor Growth

  2013cited by this paper
• Lapatinib induces p27Kip1-dependent G₁ arrest through both transcriptional and post-translational mechanisms

  2013cited by this paper
• Anisomycin induces apoptosis of glucocorticoid resistant acute lymphoblastic leukemia CEM-C1 cells via activation of mitogen-activated protein kinases p38 and JNK.

  2013cited by this paper
• miR-200c Targets a NF-κB Up-Regulated TrkB/NTF3 Autocrine Signaling Loop to Enhance Anoikis Sensitivity in Triple Negative Breast Cancer

  2012cited by this paper
• Modulation of septin and molecular motor recruitment in the microtubule environment of the Taxol‐resistant human breast cancer cell line MDA‐MB‐231

  2011cited by this paper
• Lapatinib, a Preventive/Therapeutic Agent against Mammary Cancer, Suppresses RTK-Mediated Signaling through Multiple Signaling Pathways

  2011cited by this paper
• A Pathway for the Control of Anoikis Sensitivity by E-Cadherin and Epithelial-to-Mesenchymal Transition

  2011cited by this paper
• The Misregulation of Cell Adhesion Components during Tumorigenesis: Overview and Commentary

  2010cited by this paper
• The actin filament cross-linker L-plastin confers resistance to TNF-α in MCF-7 breast cancer cells in a phosphorylation-dependent manner

  2009cited by this paper
• Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL.

  2009cited by this paper
• The Connectivity Map: Using Gene-Expression Signatures to Connect Small Molecules, Genes, and Disease

  2006cited by this paper
• [Asiaticoside inducing apoptosis of tumor cells and enhancing anti-tumor activity of vincristine].

  2004cited by this paper

• Integrative Statistical Inferences for Drug Sensitivity Biomarkers in Cancer

  2017cites this paper
• Connection Map for Compounds (CMC): A Server for Combinatorial Drug Toxicity and Efficacy Analysis

  2016cites this paper
• Identification of Biomarkers for Breast Cancer Using Databases

  2016cites this paper
• In silico docking of methyl isocyanate (MIC) and its hydrolytic product (1, 3-dimethylurea) shows significant interaction with DNA Methyltransferase 1 suggests cancer risk in Bhopal-Gas- Tragedy survivors.

  2015cites this paper
• Trastuzumab-based Retreatment after Lapatinib in Heavily Pretreated HER2 Positive Metastatic Breast Cancer: an Anatolian Society of Medical Oncology Study.

  2015cites this paper