Romidepsin and afatinib combination treatment induce synergistic anti-lymphoma effect in CTCL
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ABSTRACT:
PROVIDER: PRJNA994103 | ENA |
REPOSITORIES: ENA
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Project description:Cutaneous T-cell lymphomas (CTCL) are an aggressive group of T-cell lymphomas that present in the skin and are associated with dismal prognosis. Romidepsin is a histone deacetylase (HDAC) inhibitor that is an FDA approved systemic therapeutic indicated for the treatment of CTCL in patients who have received at least one prior systemic therapy. Romidepsin demonstrates promising single agent activity in patients with advanced stages of CTCL, however response is typically low and not durable. One method of overcoming resistance to romidepsin and improving response is through combination therapies. Here, we demonstrate that romidepsin in combination with the epidermal growth factor receptor (EGFR) inhibitor afatinib and afatinib dimaleate produce strongly synergistic anti-tumor effects in CTCL cell lines and an in vivo model of CTCL. Gene expression and western blot analysis further identifies the decreased activation of the JAK-STAT signalling pathway as a key driver of synergy in this combination. These results suggest a potential indication for FDA-approved EGFR inhibitors previously unrecognized in CTCLs as a combination therapeutic with HDAC inhibitors that can be rapidly adopted in the clinic.
2024-07-12 | GSE237167 | GEO
Project description:We demonstrate that the combination of the HDAC inhibitor, romidepsin, and the demethylating agent, azacitidine, exerts synergistic anti-proliferative effects and induction of apoptosis involving activation of the caspase cascade in CTCL cell lines as well as CD4+ T cells derived from patients with Sézary Syndrome (SS) with high tumor burden. We identified genes that were selectively induced by the combination treatment, such the tumor suppressor gene RhoB. We performed global CpG methylation-sequencing in a CTCL cell line and in patient cells. Results showed a subset of genes with a unique change in methylation profile in the combination treatment as compared to single drugs.
2016-03-30 | E-GEOD-66732 | biostudies-arrayexpress
Project description:We demonstrate that the combination of the HDAC inhibitor, romidepsin, and the demethylating agent, azacitidine, exerts synergistic anti-proliferative effects and induction of apoptosis involving activation of the caspase cascade in CTCL cell lines as well as CD4+ T cells derived from patients with Sézary Syndrome (SS) with high tumor burden. We identified genes that were selectively induced by the combination treatment, such the tumor suppressor gene RhoB.
2016-03-30 | GSE66732 | GEO
Project description:To explore the molecular mechanisms by which romidepsin potentiates the effect of talazoparib, RNA sequencing analysis of MBL2 cell lines treated with talazoparib, romidepsin, or talazoparib plus romidepsin was performed. 40% of the 2023 genes in combination were from talazoparib, whereas only 5.9% of the genes deregulated during the treatment with the combination of talazoparib plus romidepsin were from the effect of romidepsin. 94 genes were presented in all three treatment groups and included upregulation of Prdm1, Dusp5, and CD74, among others. Analysis of genes responsible for DNA repair, cell cycle arrest and apoptosis demonstrated the contribution of romidepsin to downregulation of DNA repair, the synergistic effect of romidepsin and talazoparib on downregulation of genes of cell cycle leading to cell cycle arrest, and activation of apoptosis by talazoparib predominantly.
2020-09-04 | GSE157434 | GEO
Project description:In this study, we demonstrated the synergistic effect of the mechlorethamine-romidepsin combination in cutaneous T cell lymphoma cell lines and CD4+ T cells derived from patients with Sezary Syndrome. We identify the signaling pathways specifically perturbed under treatment with mechlorethamine-romidepsin combination.
2018-12-10 | GSE110248 | GEO
Project description:Gene expression values were determined for HuT78 parental cells and cells selected with romidpesin in the presence of P-glycoprotein inhibitors. HuT78 DpVp35 cells are maintained in 35 ng/ml romidepsin with 2.5 µg/ml verapamil and HuT78 DpP100 cells are maintained in 100 ng/ml romidepsin with 1 µM valspodar To identify molecular determinants of histone deacetylase inhibitor (HDI) resistance, we selected HuT78 cutaneous T-cell lymphoma (CTCL) cells with romidepsin in the presence of P-glycoprotein (Pgp) inhibitors to prevent transporter upregulation. Resistant sublines were 250- to 385-fold resistant to romidepsin and were resistant to apoptosis induced by apicidin, entinostat, panobinostat, belinostat and vorinostat. A custom Taqman array identified increased insulin receptor (INSR) gene expression; immunoblot analysis confirmed increased expression and a 4- to 8-fold increase in mitogen activated protein kinase (MAPK) kinase (MEK) phosphorylation in resistant cells compared to parental cells. Resistant cells were exquisitely sensitive to MEK inhibitors and apoptosis correlated with restoration of proapoptotic Bim. Romidepsin combined with MEK inhibitors yielded greater apoptosis in cells expressing mutant KRAS compared to romidepsin treatment alone. Gene expression analysis of samples obtained from patients with CTCL enrolled on the NCI1312 Phase II study of romidepsin in T-cell lymphoma suggested perturbation of the MAPK pathway by romidepsin. Immunohistochemical analysis of Bim expression demonstrated decreased expression in some skin biopsies at disease progression. These findings implicate increased activation of MEK and decreased Bim expression as a resistance mechanism to HDIs, supporting combination of romidepsin with MEK inhibitors in clinical trials. Gene expression in resistant lines was compared to parental lines
2013-03-12 | E-GEOD-45018 | biostudies-arrayexpress
Project description:Tamoxifen enhances romidepsin-induced senescence in pancreatic cancer cells. We compared gene-expression profile among untreated control, romidepsin-treated, tamoxifen-treated, and romidepsin plus tamoxifen-treated Panc1 cells.
2021-08-21 | GSE182526 | GEO
Project description:TOX is a nuclear factor essential for the development of CD4+ T cells in the thymus. TOX is found to be aberrantly up-regulated in the skin biopsies and in the blood CD4+ T cells of cutaneous T cell lymphoma. The goal of this study is to identify potential transcriptional targets of TOX in CTCL by comparison between TOX shRNA transfected CTCL cells (Hut78 and HH) and control CTCL cells.
2014-04-29 | GSE57122 | GEO
Project description:TOX is a nuclear factor essential for the development of CD4+ T cells in the thymus. TOX is found to be aberrantly up-regulated in the skin biopsies and in the blood CD4+ T cells of cutaneous T cell lymphoma. The goal of this study is to identify potential transcriptional targets of TOX in CTCL by comparison between TOX shRNA transfected CTCL cells (Hut78 and HH) and control CTCL cells. Two color experiment. Lentivirus transduced control vector vs. TOX shRNA vectors on Hut78 and HH cell lines. Biological replicates: 3 control replicates, 3 shRNA tansduced replicates for each cell line.
2014-04-29 | E-GEOD-57122 | biostudies-arrayexpress
Project description:Cutaneous T-cell lymphomas (CTCL) are the most frequent primary skin lymphomas. Nevertheless, diagnosis of early disease has proven difficult due to a clinical and histological resemblance to benign inflammatory skin diseases. To address if microRNA (miRNA) profiling can discriminate CTCL from benign inflammation, we study miRNA expression in 199 patients with CTCL, peripheral T-cell lymphoma (PTL), and benign skin diseases (psoriasis and dermatitis). Using microarrays we show that the most induced- (miR-326, miR-663b, miR-711) and repressed- (miR-203, miR-205) miRNAs distinguish CTCL from benign skin diseases with > 90% accuracy in a training set of 90 samples and a test set of 58 blinded samples. These miRNAs also distinguish malignant and benign lesions in an independent set of 50 patients with PTL and skin inflammation and in experimental human xenograft mouse models of psoriasis and CTCL. Q-RT-PCR analysis of 104 patients with CTCL and benign skin disorders validates differential expression of 4 out of the 5 miRNAs and confirms previous reports on miR-155 in CTCL. A q-RT-PCR-based classifier consisting of miR-155, miR-203, and miR-205 distinguishes CTCL from benign disorders with high specificity, sensitivity, and a classification accuracy of 95% indicating that miRNAs have a high diagnostic potential in CTCL.
2011-11-22 | GSE31408 | GEO