Acquired resistance to lapatinib
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE38376 | GEO | 2012/06/30
SECONDARY ACCESSION(S): PRJNA167755
REPOSITORIES: GEO
Similar Datasets
Project description: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.
2011-09-19 | E-GEOD-16179 | biostudies-arrayexpress
Project description:Gene expression profiling were examined by Human HT-12 v4.0 Expression BeadChip arrays in SKBR3 and BT474 cells treated with HER2 inhibitor lapatinib or CDK7 inhibitor THZ1.
2021-05-21 | GSE129254 | GEO
Project description:In SKBR3 cells, simultaneous targeting of RARM-kM-1 with all-trans retinoic acid (ATRA) and HER2 with lapatinib results in synergistic anti-tumor responses. SKBR3 cells were treated with vehicle (DMSO), lapatinib (100 nM), ATRA (100 nM) or lapatinib+ATRA for 36 hours and miRNA expression profile was determined by one-color Agilent microarray experiments.
2015-04-30 | E-MTAB-3097 | biostudies-arrayexpress
Project description:To explore the broader impact of kinase inhibitors on breast cancer cells, SKBR3/HER2+ cells were treated with two small molecule drugs, i.e., Lapatinib (10 uM) - a Tyr kinase inhibitor, and Ipatasertib (1 uM) - a Ser/Thr kinase inhibitor. Serum-starved cells (24 h) were exposed for 36 h to Lapatinib/EGF or a combination of Lapatinib/Ipatasertib/EGF. EGF - only stimulated cells were used as control. The EGF concentration was 10 nM throughout all experiments. Proteomic profiles of nuclear and cytoplasmic cell fractions of treated vs non-treated cells were generated by nano-LC-MS/MS using an Orbitrap QE instrument.
2024-08-23 | PXD051094 | Pride
Project description:Transcriptional profiling of human HER2-positive BT474 breast cancer cells comparing control untreated cancer cells with lapatinib-resistant clone established by chronic treatment with lapatinib Two-condition experiment, parental cells vs. lapatinib-resistant (LR) clone.
2013-10-31 | E-GEOD-51889 | biostudies-arrayexpress
Project description:Ablation of ERRalpha significantly delays ERBB2-induced mammary tumorigenesis and ERRalpha regulates genes of the ERBB2 amplicon. To further investigate the relationship between ERRalpha activity and RTK signaling, we depleted ERRalpha in SKBr3 cells upon serum starvation, EGF treatment or heregulin treatment. Inhibition of ERBB2 signaling using the RTK inhibitor lapatinib impacts on ERRalpha stability. Since we have shown that the development of lapatinib-resistance restaures the expression of ERRalpha in breast cancer cells, we performed depletion of ERRalpha in SKBr3 cells that have developped resistance to lapatinib treatment in order to identify a potential reprogramming of ERRa transcriptional activity associated to lapatinib resistance, For the study of growth factor effec on ERRalpha activity, total RNA was obtained from human SKBr3 breast cancer cells cultured in DMEM deprived of FBS (starved) for 24 hours and treated with PBS, EGF (100uM) or Heregulin (100uM) for an additional 24h. Cells were transfected with siRNA against ERRalpha or with siControl for 60 hours prior to harvesting. For the effect of ERRalpha in lapatinib resistance cells, parental SKBr3 cells (pSKBr3) and Lapatinib-resistant cells (LRSKBr3, maintained in 2uM lapatinib) were transfected with siControl (siC) or siERRalpha for 60 hours prior to harvesting and RNA extraction
2016-06-15 | E-GEOD-81546 | biostudies-arrayexpress
Project description:Acquired drug resistance prevents targeted cancer therapy from achieving stable and complete responses. Emerging evidence implicates a key role for nonmutational mechanisms including changes in cell state during early stages of acquired drug resistance. Targeting nonmutational resistance may therefore present a therapeutic opportunity to eliminate residual surviving tumor cells and impede relapse. A variety of cancer cell lines harbor quiescent, reversibly drug-tolerant âpersisterâ cells which survive cytotoxic drugs including targeted therapies and chemotherapies. These persister cells survive drug through nonmutational mechanisms which are poorly understood. Specifically targeting persister cells is a promising strategy to prevent tumor relapse. We sought to identify therapeutically exploitable vulnerabilities in persister cells using the HER2-amplified breast cancer line BT474 as an experimental model. Similar to other persister cell models, upon treatment with the HER2 inhibitor lapatinib (2uM concentration) for nine or more days, the majority of BT474 cells die, revealing a small population of quiescent surviving persister cells. Removal of lapatinib allows the persister cells to regrow and to re-acquire sensitivity to lapatinib. Subsequent lapatinib treatment re-derives persister cells. The reversibility of persister cell drug resistance indicates a nonmutational resistance mechanism. Here we provide RNAseq gene expression profiling data generated from parental BT474 cells compared to BT474 persister cells generated from nine days of treatment with 2 uM lapatinib. These data can be used to identify genes and pathways which are upregulated in persister cells, revealing potential therapeutic targets. 3 biological replicates of BT474 persister cells, two biological replicates of BT474 parental cells
2016-07-28 | E-GEOD-84896 | biostudies-arrayexpress
Project description:Ablation of ERRalpha significantly delays ERBB2-induced mammary tumorigenesis and ERRalpha regulates genes of the ERBB2 amplicon. To further investigate the relationship between ERRalpha activity and RTK signaling, we mapped ERRalpha binding sites in SKBr3 cells upon EGF treatment or heregulin treatment. Inhibition of ERBB2 signaling using the RTK inhibitor lapatinib impacts on ERRalpha stability, while cells resistant to lapatinib treatment exhibit restored ERRalpha expression. We therefore mapped ERRalpha binding sites in parental (sensitive) cells (pSKBr3) as well as in lapatinib-resistant cells (LRSKBr3). ChIP-Seq analysis of ERRalpha binding profile in SKBr3 or BT-474 breast cancer cells.
2016-06-15 | E-GEOD-81651 | biostudies-arrayexpress
Project description:Acquired drug resistance prevents targeted cancer therapy from achieving stable and complete responses. Emerging evidence implicates a key role for nonmutational mechanisms including changes in cell state during early stages of acquired drug resistance. Targeting nonmutational resistance may therefore present a therapeutic opportunity to eliminate residual surviving tumor cells and impede relapse. A variety of cancer cell lines harbor quiescent, reversibly drug-tolerant “persister” cells which survive cytotoxic drugs including targeted therapies and chemotherapies. These persister cells survive drug through nonmutational mechanisms which are poorly understood. Specifically targeting persister cells is a promising strategy to prevent tumor relapse. We sought to identify therapeutically exploitable vulnerabilities in persister cells using the HER2-amplified breast cancer line BT474 as an experimental model. Similar to other persister cell models, upon treatment with the HER2 inhibitor lapatinib (2uM concentration) for nine or more days, the majority of BT474 cells die, revealing a small population of quiescent surviving persister cells. Removal of lapatinib allows the persister cells to regrow and to re-acquire sensitivity to lapatinib. Subsequent lapatinib treatment re-derives persister cells. The reversibility of persister cell drug resistance indicates a nonmutational resistance mechanism. Here we provide RNAseq gene expression profiling data generated from parental BT474 cells compared to BT474 persister cells generated from nine days of treatment with 2 uM lapatinib. These data can be used to identify genes and pathways which are upregulated in persister cells, revealing potential therapeutic targets.
2016-07-28 | GSE84896 | GEO
Project description:Despite effective strategies, therapy resistance in HER2+ breast cancer remains a challenge. While the Mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Using HER2+ breast cancer parental (P) cell models (AU565, SKBR3, and UACC812), we have established anti-HER2-resistant derivatives made resistant to lapatinib (LR) or lapatinib plus trastuzumab (LTR). We performed RNA-seq on these resistant models and the P cells treated with lapatinib or lapatinib plus trastuzumaba for 24 h. We found that the average expression of the key genes in the MVA pathway, as a surrogate for pathway activity, was dramatically reduced in P cells with short-term treatment. In contrast, expression was restored or further upregulated relative to P cells in all three resistant (LR/LTR) models. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the n-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of resistant cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP), but not by cholesterol. Activated YAP/TAZ and mTORC1 signaling and their downstream target gene product Survivin were inhibited by MVA blockade especially in the LR/LTR models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated S6 levels despite blockade of the MVA. The MVA may provide alternative signaling leading to cell survival and resistance when HER2 is blocked by activating YAP/TAZ-mTORC1-Survivin signaling suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy and warrant further clinical investigation.
2020-04-04 | GSE132055 | GEO