Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

BT474 and BT474-J4 microarray data

ABSTRACT: These data provide scientific information to understand the mechanism of action of lapatinib resistance in HER2-positive patients and to test the combination of HER2-targeted agents and GSK1363089 (foretinib) in the clinic by using an acquired lapatinib-resistant cell line. Cell lines (BT474, an HER2-positive and lapatinib-sensitive cell line; BT474-J4, an acquired lapatinib-resistant cell line) were treated with lapatinib alone (1uM), foretinib (GSK1363089) alone (0.1 uM), a combination of lapatinib (1 uM) and foretinib (0.1 uM), or DMSO control for 24 hours. Triplicates were performed.

ORGANISM(S): Homo sapiens

SUBMITTER: Yuan Liu

PROVIDER: E-GEOD-16179 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL.

Liu Li L Greger James J Shi Hong H Liu Yuan Y Greshock Joel J Annan Roland R Halsey Wendy W Sathe Ganesh M GM Martin Anne-Marie AM Gilmer Tona M TM

Cancer research 20090811 17

HER2-directed therapies, such as trastuzumab and lapatinib, are important treatments for breast cancer. However, some tumors do not respond or develop resistance to these agents. We isolated and characterized multiple lapatinib-resistant, HER2-positive, estrogen receptor (ER)-positive breast cancer clones derived from lapatinib-sensitive BT474 cells by chronic exposure to lapatinib. We show overexpression of AXL as a novel mechanism of acquired resistance to HER2-targeted agents in these models. ...[more]

PMID: 19671800

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Project description:Breast cancers with HER2 overexpression are sensitive to drugs targeting the receptor or its kinase activity. HER2-targeting drugs are initially effective against HER2- positive breast cancer, but resistance inevitably occurs. We previously found that nuclear factor kappa B is hyper-activated in the subset of HER-2 positive breast cancer cells and tissue specimens. In this study, we report that constitutively active NF-ÎºB rendered HER2-positive cancer cells resistant to anti-HER2 drugs, and cells selected for Lapatinib resistance up-regulated NF-ÎºB. In both circumstances, cells were anti-apoptotic and grew rapidly as xenografts. Lapatinib-resistant cells were refractory to HER2 and NF-ÎºB inhibitors alone but were sensitive to their combination, suggesting a novel therapeutic strategy. A subset of NF-ÎºB-responsive genes was overexpressed in HER2-positive and triple-negative breast cancers, and patients with this NF-ÎºB signature had poor clinical outcome. Anti-HER2 drug resistance may be a consequence of NF-ÎºB activation, and selection for resistance results in NF-ÎºB activation, suggesting this transcription factor is central to oncogenesis and drug resistance. Clinically, the combined targeting of HER2 and NF-ÎºB suggests a potential treatment paradigm for patients who relapse after anti-HER2 therapy. Patients with these cancers may be treated by simultaneously suppressing HER2 signaling and NF-ÎºB activation. We used microarrays to detail the gene expression differences underlying the characterictic survival differences between the SKR6, SKR6-Vector, SKR6CA, and SKR6LR cell lines, which are defined as follows: SKR6: A clonal derivative of SKBR3 cells isolated by fluorescence-activated cell sorting (FACS) to enrich for elevated HER2 levels, SKR6CA: SKR6 cells retrovirally transduced with constitutively active NF-ÎºB relA/p65 (CAp65) and selected with puromycin, SKR6 vector: SKR6 cells transduced with the pQCXIP empty retroviral vector and selected with puromycin, and SKR6LR: SKR6 cells treated with increasing lapatinib concentrations (0.2 to 5 Î¼M) for several months. We sorted SKBR-3 cells by fluorescence-activated cell sorting (FACS) to enriched for cell population with elevated HER2 expression, which we termed SKR6. The following cell lines were then created from SKR6 cells: SKR6CA: SKR6 cells retrovirally transduced with constitutively active NF-ÎºB relA/p65 (CAp65), SKR6 vector: SKR6 cells transduced with the pQCXIP empty retroviral vector and selected with puromycin, and SKR6LR: SKR6 cells treated with increasing lapatinib concentrations (0.2 to 5 Î¼M) for several months.

Dataset Information

BT474 and BT474-J4 microarray data

Publications

Novel mechanism of lapatinib resistance in HER2-positive breast tumor cells: activation of AXL.

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