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Targeted inhibition of LIFR enhances therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

ABSTRACT: Targeted inhibition of LIFR enhances therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

PROVIDER: PRJNA685420 | ENA |

REPOSITORIES: ENA

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Targeted inhibition of LIFR enhances therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

Project description:Here, we examined the therapeutic utility of EC359 in improving the therapeutic efficacy of HDACi in TNBC models. BT-549 cells were treated with vehicle (DMSO), EC359, HDACi(Vorinostat), EC359+HDACi and the RNA was isolated and utilized for RNA-seq analysis. Our results demonstrated that the beneficial effect of the EC359+HDACi involves regulation of multiple genes that involved in several pathways including apoptosis, metabolism and cell cycle.

2021-12-02 | GSE163249 | GEO

HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma

Project description:HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma

| PRJNA525852 | ENA

HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma

Project description:Purpose: The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. The current study has used multi-omics approaches and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance. Experimental Design: Mass spectrometry-based proteomics and RNA-Seq was used to identify the signaling pathways involved in the escape of uveal melanoma cells from MEK inhibitor therapy. Mechanistic studies were performed to evaluate the escape pathways identified and the efficacy of the MEK-HDAC inhibitor combination was demonstrated in multiple in vivo xenograft models of uveal melanoma. Results: We identified a number of putative escape pathways that were upregulated following MEK inhibition including the PI3K/AKT pathway, ROR1/2 and IGF1R signaling. MEK inhibition was also associated with a widespread increase in GPCR expression, particularly the Endothelin B receptor and that this contributed to therapeutic escape through YAP signaling. A screen of 289 clinical grade compounds identified HDAC inhibitors as potential candidates that suppressed the adaptive YAP and AKT signaling that followed MEK inhibition. In vivo xenograft studies revealed the MEK-HDAC inhibitor combination to outperform either agent alone, leading to a long-term decrease of tumor growth and the suppression of adaptive PI3K/AKT and YAP signaling. Conclusions Together our studies have identified GPCR-mediated YAP activation and RTK-driven AKT signaling as key pathways involved in the escape of uveal melanoma cells from MEK inhibition. We further demonstrate that HDAC inhibition is a promising combination partner for MEK inhibitors in uveal melanoma.

2020-05-26 | PXD013988 | Pride

LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

Project description: Not available

| S-EPMC8556368 | biostudies-literature

HDAC inhibitors in synovial sarcoma cells

Project description:Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-Seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell cycle arrest, neuronal differentiation and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb-group targets were reactivated including tumor suppressor CDKN2A, and pro-apoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and pro-apoptotic factors BIK, BIM and BMF were important to apoptosis induction following HDAC-inhibition in synovial sarcoma

| EGAS00001002637 | EGA

Antagonism of IAPs enhances CAR T cell efficacy

Project description:Antagonism of IAPs enhances CAR T cell efficacy

| PRJNA510825 | ENA

HDAC inhibition enhances the in vivo efficacy of MEK inhibitor therapy in uveal melanoma

Project description:Purpose: The clinical use of MEK inhibitors in uveal melanoma is limited by the rapid acquisition of resistance. The current study has used unbiased multi-omics and drug screens to identify the pan-HDAC inhibitor panobinostat as an effective strategy to limit MEK inhibitor resistance.

2019-06-11 | GSE127948 | GEO

IL-17A increases doxorubicin efficacy in triple negative breast cancer

Project description:IL-17A increases doxorubicin efficacy in triple negative breast cancer

| PRJNA846314 | ENA

HER3 targeting augments the efficacy of panobinostat in claudin-low triple-negative breast cancer cells

Project description:Patients with triple-negative breast cancer (TNBC) have a poor prognosis and high relapse rate due to limited therapeutic options. This study was conducted to determine the mechanisms of action of panobinostat, a pan-inhibitor of histone deacetylase (HDAC) and FDA-approved medication for multiple myeloma, in TNBC and to provide a rationale for effective drug combinations against this aggressive disease. RNA sequencing analyses of the claudin-low (CL) TNBC (MDA-MB-231) cells untreated or treated with panobinostat were performed to identify the differentially expressed genes. Adaptive alterations in gene expression were analyzed and validated in additional CL TNBC cells. Tumor xenograft models were used to test the in vivo antitumor activity of panobinostat alone or its combinations with gefitinib, an EGFR-tyrosine kinase inhibitor (TKI). Panobinostat potently inhibited proliferation and induced apoptosis in all TNBC cells tested. However, in CL TNBC cells, this HDAC inhibitor markedly enhanced expression of HER3, which interacted with EGFR to activate both receptors and Akt signaling pathways. Combinations of panobinostat and gefitinib synergistically suppressed CL TNBC cell proliferation and promoted apoptosis in vitro and in vivo. Upregulation of HER3 compromises the efficacy of panobinostat in CL TNBC. Inactivation of HER3 combined with panobinostat represents a practical approach to combat CL TNBC.

2023-07-05 | GSE236280 | GEO

mTOR and HDAC inhibitors converge on the TXNIP/thioredoxin pathway to cause catastrophic oxidative stress and regression of RAS-driven tumors

Project description:mTOR and HDAC inhibitors induce cell death of malignant peripheral nerve sheath tumors (MPNSTs) in vitro, and in vivo We performed microarray analysis of mTOR and HDAC inhibition alone and in combination 24 hours after treatment, prior to induction of cell death, to identify transcriptional changes that might be mechanistic drivers of the therapeutic efficacy

2017-10-23 | GSE84205 | GEO

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