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DUSP6 inhibition overcomes Neuregulin/HER3-driven therapy resistance in HER2+ breast cancer [BT474]

ABSTRACT: To investigate transcriptomic changes during development of resistance to lapatinib in a HER2+ breast cancer cell line We performed gene expression profiling analysis using data obtained from RNA-seq of 4 different stage of development of lapatinib resistance in a HER2+ breast cancer cell line

ORGANISM(S): Homo sapiens

PROVIDER: GSE231525 | GEO | 2024/04/13

REPOSITORIES: GEO

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DUSP6 inhibition overcomes Neuregulin/HER3-driven therapy resistance in HER2+ breast cancer [MDA]

Project description:To investigate transcriptomic changes regulated by DUSP6 in a HER2+ breast cancer cell line We performed gene expression profiling analysis using data obtained from RNA-seq of SCR vs DUSP6 KD MDA-MB-453 cells

2024-04-13 | GSE231524 | GEO

DUSP6 inhibition overcomes Neuregulin/HER3-driven therapy resistance in HER2+ breast cancer [BT474]

Project description:DUSP6 inhibition overcomes Neuregulin/HER3-driven therapy resistance in HER2+ breast cancer [BT474]

| PRJNA966203 | ENA

BT474 and BT474-J4 microarray data

2011-09-20 | GSE16179 | GEO

BT474 and BT474-J4 microarray data

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

DUSP6 inhibition overcomes Neuregulin/HER3-driven therapy resistance in HER2+ breast cancer [MDA]

Project description:DUSP6 inhibition overcomes Neuregulin/HER3-driven therapy resistance in HER2+ breast cancer [MDA]

| PRJNA966202 | ENA

DUSP6 inhibition overcomes Neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer

Project description:Despite clinical benefits of tyrosine kinase inhibitors (TKIs) in cancer, most tumors can reactivate proliferation under TKI therapy. Here we present transcriptional profiling of HER2+ breast cancer cells transitioning from dormant drug tolerant cells to re-proliferating cells under continuous HER2 inhibitor (HER2i) therapy. Focusing on phosphatases, expression of dual-specificity phosphatase DUSP6 was found inhibited in dormant cells, but strongly induced upon re-growth. DUSP6 expression also selectively associated with poor patient survival in HER2+ breast cancers. DUSP6 overexpression conferred apoptosis resistance, whereas its pharmacological blockade prevented therapy tolerance development under HER2i therapy. DUSP6 targeting also synergized with clinically used HER2i combination therapies. Mechanistically DUSP6 is a positive regulator of HER3 expression, and its impact on HER2i tolerance was mediated by neuregulin-HER3 axis. In vivo, genetic targeting of DUSP6 reduced tumor growth in brain metastasis model, whereas its pharmacological targeting induced synthetic lethal therapeutic effect in combination with HER2i. Collectively this work demonstrates that DUSP6 drives escape from HER2i-induced dormancy, and that DUSP6 is a druggable target to overcome HER3-driven TKI resistance.

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SNP arrays of BT474 Latpatinib and/or Trastuzumab resistant cell lines for copy number analysis.

Project description:Targeting HER2 with lapatinib (L), trastuzumab (T), or the LT combination, is effective in HER2+ breast cancer (BC), but de novo and acquired resistance commonly occur. The purpose of this experiment was to investigate the somatic alterations found in Lapatinib and/or Trastuzumab resistant cells lines.

2019-06-21 | GSE83608 | GEO

DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer

Project description:DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer

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Gene expression profiling of drug-tolerant persister BT474 breast cancer cells derived from lapatinib treatment

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

DUSP6 inhibition overcomes neuregulin/HER3-driven therapy tolerance in HER2+ breast cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-04-12 | GSE231526 | GEO