Ontology highlight
ABSTRACT:
PROVIDER: PRJNA610037 | ENA |
REPOSITORIES: ENA
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Project description:To determine the global transcriptome changes in mantle cell lymphoma cells following treatment with the BET bromodomain antagonist, JQ1 Mantle Cell Lymphoma (MCL) cells exhibit increased B cell receptor and NFkB activities. The BET protein BRD4 is essential for the transcriptional activity of NFkB. Here, we demonstrate that treatment with the BET protein bromodomain antagonist (BA) JQ1 attenuates MYC and CDK4/6, inhibits the nuclear RelA levels and the expression of NFκB target genes including Brutonâs Tyrosine Kinase (BTK) in MCL cells. While lowering the levels of the anti-apoptotic BCL2 family proteins, BA treatment induces the pro-apoptotic protein BIM and exerts dose-dependent lethality against cultured and primary MCL cells. Co-treatment with BA and the BTK inhibitor ibrutinib synergistically induces apoptosis of MCL cells. Compared to each agent alone, co-treatment with BA and ibrutinib markedly improved the median survival of mice engrafted with the MCL cells. BA treatment also induced apoptosis of the in vitro isolated, ibrutinib-resistant MCL cells which overexpress CDK6, BCL2, Bcl-xL, XIAP and AKT, but lack ibrutinib resistance-conferring BTK mutation. Co-treatment with BA and panobinostat (pan-histone deacetylase inhibitor) or palbociclib (CDK4/6 inhibitor) or ABT-199 (BCL2 antagonist) synergistically induced apoptosis of the ibrutinib-resistant MCL cells. These findings highlight and support further in vivo evaluation of the efficacy of the BA-based combinations with these agents against MCL, including ibrutinib-resistant MCL. MO2058 cells treated with vehicle, 250 nM or 1000 nM JQ1 for 8 hours. Samples were acquired and analyzed in duplicate.
2015-12-31 | E-GEOD-70651 | biostudies-arrayexpress
Project description:CDK4/6 kinase inhibitors have shown great promise in clinical trials in various cancer types and have recently entered clinical trial for advanced prostate cancer. Although patients are expected to respond well to this class of drugs, development of resistance in some patients is anticipated. To pre-empt this and study how prostate cancer may evade CDK4/6 inhibition, new resistance models were generated from LNCaP and LAPC4 prostate cancer cells cells by prolonged culturing in presence of 0.5uM palbociclib. A shotgun phosphoproteomics approach was utilized and integrated with RNA sequencing data to unravel the molecular underpinnings of acquired resistance to palbociclib and resultant broad CDK4/6 inhibitor resistance.
2018-05-16 | PXD006561 | Pride
Project description:Covalent Bruton's tyrosine kinase inhibitors (BTKis) have transformed the treatment of B-cell non-Hodgkin lymphoma (B-NHL), including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but their activity has been limited by off-target toxicity and acquired drug resistance. TG-1701 is a novel irreversible and highly specific BTKi being presently under study in a phase 1 clinical trial in patients with relapsed/refractory B-NHL alone and in combination with ublituximab, a CD20 antibody, and umbralisib, a dual PI3Kδ and CK1ε inhibitor. Here we show, for the first time that phosphoproteomic analysis of CLL patients receiving a BTKi (TG-1701) led to a non-supervised clustering that matched the clinical outcomes and separated a group of “responders” from a group of “non-responders”. This clustering was based on a selected list of 96 phosphosites, with Ikaros-Ser442/445 phosphorylation as a potential marker for TG-1701 efficacy. RNA-seq analysis followed by qPCR and western blot validation further revealed that TG-1701 treatment blunted the Ikaros gene signature only in responder patients, as well as in BTKi-sensitive, but not BTKi-insensitive, B-NHL cell lines and xenografts. Importantly, and in contrast with ibrutinib, TG-1701 did not impair FcγR-driven antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) triggered by the anti-CD20 antibodies rituximab and ublituximab in a multicellular MCL co-culture system. In addition, TG-1701 cooperated with ublituximab coupled to umbralisib (also referred as the U2 regimen) in reducing the tumor growth in both ibrutinib-sensitive and ibrutinib-insensitive mouse models of MCL. Altogether, these data validate phosphoproteomic as a broken thread to omics analysis in the clinic and support the use of TG-1701-U2 combination in R/R B-NHL patients, irrespective of prior response to ibrutinib.
2021-09-22 | PXD023231 | Pride
Project description:We report scRNA-seq data showing the effect of palbociclib treatment on medulloblastomas that form in Smo-mutant mice. We generate tumor-bearing mice by breeding hGFAP-Cre and SmoM2 mouse lines to prodce tumor-prone progeny heterozygous for both transgenes (G-Smo mice). We compare tumors from untreated G-Smo mice to tumors from G-Smo ice treated with nanoparticle--delievered palbociclib, using Drop-seq-based scRNA-seq.
2021-11-16 | GSE188672 | GEO
Project description:CDK4/6 kinase inhibitors have shown great promise in clinical trials in various cancer types and have recently entered clinical trial for advanced prostate cancer. Although patients are expected to respond well to this class of drugs, development of resistance in some patients is anticipated. To pre-empt this and study how prostate cancer may evade CDK4/6 inhibition, new resistance models were generated from LNCaP and LAPC4 prostate cancer cells cells by prolonged culturing in presence of 0.5uM palbociclib. RNA sequencing data was integrated with phospho-proteomics to unravel the molecular underpinnings of acquired resistance to palbociclib and resultant broad CDK4/6 inhibitor resistance.
2018-05-31 | GSE99675 | GEO
Project description:We used single-cell RNA sequencing (scRNA seq) to elucidate the alterations of tumor microenvironment upon combined treatment of lenvatinib and palbociclib (combo).
2023-09-27 | GSE218010 | GEO
Project description:Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in developed countries. Ibrutinib (PCI-32765), a specific and irreversible inhibitor of Bruton's Tyrosine Kinase (BTK) represents a major step forward in the treatment of CLL. We have undertaken a detailed analysis of the changes happening to the chromatin structure in CLL cells from patients continuously receiving oral doses of ibrutinib. ChIP-seq has been performed for H3K4me3, H3K27ac, H3K27me3 and EZH2 up to 56 days following the beginning of the treatment. We observed that Ibrutinib-dependent lymphocytosis correlates with a global and transient recruitment of EZH2 to active cis-regulatory elements and increased H3K27me3.
2019-06-01 | E-MTAB-6410 | biostudies-arrayexpress