A6634cf4-6851-444e-bd34-1c5ec47ea7a9 - samples
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ABSTRACT:
PROVIDER: EGAD00001008685 | EGA |
REPOSITORIES: EGA
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Project description:We examined the CLL cells transcriptome data of six patients who fail to clear their leukemia cells and develop progressive disease on venetoclax therapy. Methods: CLL cells were collected prior to venetoclax therapy (Sample Collection 1 (SC1)) and then more than 1 year later (Sample Collection 2 (SC2)). Negative isolation of CLL cells to ≥95% purity was performed prior to RNA isolation.
2022-06-23 | GSE192685 | GEO
Project description:Most BRAF-mutant melanoma tumors respond initially to BRAFi/MEKi therapy, although few patients have durable long-term responses to these agents. The goal of this study was to utilize an unbiased computational approach to identify inhibitors which reverse an experimentally derived BRAFi resistance gene expression signature. Using this approach, we predicted that ibrutinib, a BTK inhibitor, effectively reverses this signature, and we demonstrate experimentally that ibrutinib re-sensitizes a subset of BRAFi-resistant melanoma cells to vemurafenib. Ibrutinib is used clinically as a BTK inhibitor; however, neither BTK deletion nor treatment with acalabrutinib, an analog of ibrutinib with reduced off-target activity, re-sensitized cells to vemurafenib. These data suggest that ibrutinib acts through a BTK-independent mechanism in vemurafenib re-sensitization. To better understand this mechanism, we analyzed the transcriptional profile of ibrutinib-treated BRAFi-resistant melanoma cells and found that the transcriptional profile of ibrutinib was highly similar to that of multiple SRC kinase inhibitors. Since ibrutinib, but not acalabrutinib, has significant off-target activity against multiple SRC family kinases, it suggests that ibrutinib may be acting through this mechanism. Furthermore, genes either upregulated or downregulated by ibrutinib treatment are enriched with YAP1 target genes and we experimentally demonstrate that ibrutinib, but not acalabrutinib, reduces YAP1 activity in BRAFi-resistant melanoma cells. Taken together, these data suggest that ibrutinib, or other SRC family kinase inhibitors, may be useful for treating some BRAFi/MEKi-refractory melanoma tumors.
2020-02-27 | GSE145990 | GEO
Project description:Early-phase clinical trials of Bruton’s tyrosine kinase (BTK) degraders have demonstrated efficacy in patients with BTK inhibitor-resistant chronic lymphocytic leukemia (CLL). How clinical resistance to BTK degraders arises is unknown. Here we sequenced serial CLL samples from patients enrolled in the phase I trials of zelebrudomide and bexobrutideg and observed recurrent expansion of preexisting BTK A428D mutations at relapse. Unlike previously studied BTK inhibitor resistance mutations, BTK A428D conferred pan-resistance to BTK inhibitors and degraders. In the absence of BTK-directed therapies, however, cells bearing BTK A428D exhibited a competitive disadvantage. A crystal structure of BTK A428D revealed that the mutant aspartate confers broad resistance to ATP-competitive small molecules by obstructing essential drug contacts with the kinase hinge. Combining BTK degraders with venetoclax mitigated expansion of BTK A428D. These results provide the basis for clinical resistance to BTK degraders and will inform therapy sequencing and the development of next-generation degrader therapies.
2026-05-08 | GSE330399 | GEO
Project description:Disparate mechanisms of pathogenesis have thwarted implementation of precision medicine approaches for the treatment of diffuse large B-cell lymphoma (DLBCL), the most frequently diagnosed hematologic malignancy in the United States. Though curable with combination chemoimmunotherapy in many newly diagnosed patients, DLBCL carries persistently poor prognosis for those with relapsed or refractory (rel/ref) disease, despite recent advances in immunotherapy. Here, we build on recent findings implicating gain-of-function mutations in the BCL10 signaling protein as drivers of resistance to Bruton’s tyrosine kinase (BTK) inhibitors. We show mutant BCL10-driven DLBCL models are resistant to multiple additional drug classes, demonstrating urgency to derive mechanistically rooted treatment strategies to overcome undruggable BCL10 mutants that form stable BTK-independent signaling filaments upstream of NF-kB activation. BCL10 mutants promote a cytokine-reinforced positive feedback loop of lymphomagenesis driving not just NF-kB but multiple additional pathways converging on diffuse activation of oncogenic transcription factors. Up-regulation of multiple anti-apoptotic genes promotes increased mitochondrial membrane potential, a key factor underlying multidrug resistance. Increased expression of BCL2, BCL2L1 (BCL-XL), and BCL2A1 (BFL1) drives resistance to the BCL2 inhibitor venetoclax, but further investigation revealed expression is overcome by the potent non-covalent BTK inhibitor pirtobrutinib. Venetoclax plus pirtobrutinib synergized in overcoming resistance and potently killed BCL10- mutant DLBCL tumors in vitro and in vivo. BTK therefore retains key roles protecting DLBCL tumors from apoptosis even when direct downstream activation of the BCL10 signaling complex activates NF-kB independently.
2025-02-12 | GSE267421 | GEO
Project description:In chronic lymphocytic leukemia, measurable residual disease (MRD) depth following fixed-duration treatment is associated with progression-free survival (PFS). Often, MRD is reported as a static parameter, but successive MRD measurements may more accurately capture MRD dynamics and reveal valuable prognostic information. We used our recently developed IGHV leader-based NGS assay to measure MRD at four timepoints in 60 patients treated in the HOVON-139/GIVE trial, in which previously untreated patients received one year induction treatment with obinutuzumab and venetoclax, followed by randomization to consolidation treatment with venetoclax or MRD-conditional consolidation. Induction treatment resulted in MRD undetectability (<10-5) in 93% of assessed patients, with 85% and 74% of patients retaining MRD undetectability at six and twelve months after randomization. Uniquely, we measured MRD at a very early timepoint, during the fourth week of venetoclax ramp-up after obinutuzumab pre-induction. Here, MRD levels showed large interindividual variation, and, importantly, were associated with the probability of achieving MRD undetectability after induction treatment, MRD conversion after randomization and PFS. Additionally, the IGHV leader-based NGS assay allows characterization of the healthy background IGHV repertoire. Of note, venetoclax consolidation treatment, compared to no consolidation treatment, significantly impaired polyclonal IGHV repertoire reconstitution after induction treatment with venetoclax and obinituzumab.
2024-03-01 | GSE225043 | GEO
Project description:Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice autoimmune indications. However, our current knowledge of the role of BTK in immune competence has been gathered in the context of genetic inactivation of btk in both mice and man. Using the novel BTK inhibitor PF-303, we model the clinical phenotype of BTK inhibition by systematically examining the impact of PF-303 on the mature immune system in mice. We implicate BTK in tonic BCR signaling, demonstrate dependence of the T3 B cell subset and IgM surface expression on BTK activity, and find that B1 cells survive and function independently of BTK. While BTK inhibition does not impact humoral memory survival, antigen-driven clonal expansion of memory B cells and antibody secreting cell generation are inhibited. These data define the role of BTK in the mature immune system and mechanistically predict the clinical phenotype of BTK inhibition. We used Affymetrix genechips to profile the transcriptional changes downstream of BTK inhibition after in vivo B-cell activation by anti-IgD Mice were injected with the novel BTK inhibitor PF-303 2 hours prior to anti-IgD mediated in vivo B-cell activation; B-cells where harvested 2 hours after anti-IgD activation and RNA isolated.
2014-08-01 | E-GEOD-56483 | biostudies-arrayexpress
Project description:Gene expression profile (GEP) was analyzed from cultured bone marrow (BM) samples from patients with bortezomib responsive versus bortezomib resistant myeloma after 6-8 hours incubation in vitro with bortezomib 2 µg/ml or with PBS. Case D also had a fresh BM sample taken 75 minutes after IV injection of bortezomib.
2013-11-01 | GSE51940 | GEO
Project description:We performed single-cell RNA sequencing of a lymphoma (OCI-Ly18) subcutaneous tumor harvested from NSG mice two weeks after infusion with CART19 plus DMSO or CART19 plus Venetoclax (Suppl. Fig. 3A). Lymphoma cells with shared gene expression profiles were clustered using uniform manifold and approximation (UMAP) analysis. We identified six clusters characterized by different cell-cycle phases (Suppl. Fig. 3B), including one G1-dominant cluster, two S clusters, one G1/G2 cluster, one G2/M cluster, and an M cluster with high Ki67 expression. First, we observed a substantially lower proportion of cells assigned to G1-dom in the CART19/venetoclax-treated condition (8.4%) than in the CART19-treated condition (24%). These indicated a prevalent depletion of the G1-dom cluster by the addition of venetoclax (Suppl. Fig. 4C). In accordance with recent reports that venetoclax can induce cell cycle arrest and death in tumor cells in G1 39, these results suggest that venetoclax treatment also enhances CART’s anti-tumor efficacy by hindering the progression of cell cycle. Interestingly, the “G1-dominant (G1-dom)” and the additional “MKI67hi” cluster (high proliferative cells) showed significant enrichment of genes corresponding to interferon-gamma responsiveness, suggesting that the cells of these two clusters might have been interacting with CART cells (Suppl. Fig. 4D). Of note, by performing GO enrichment analysis with differentially expressed genes (DEGs) between CART19 and CART19/venetoclax combination in the MKI67hi cluster that represent a rapidly proliferating tumor subpopulation, we identified several pathways, including enrichment of the negative regulation of the G2/M phase transition in the CART19/venetoclax-treatment condition in the MKI67hi cluster (Suppl. Fig. 4E and 4F). Taken together, these data implicate that venetoclax treatment enhances CART-mediated tumor killing by promoting tumor apoptosis and inhibiting the cell cycle in cancer cells while also enhancing the interferon responses in neoplastic B-cells when engaging CART cells.
2022-02-03 | GSE195814 | GEO
Project description:Gene expression profiling from skin tissue samples. Pre-treatment = sample taken before any treatment at the time of SPTL diagnosis, post-treatment 1 = sample taken during treatment after 3 to 6 months of diagnosis and post-treatment 2 = sample taken during treatment after 6 to 12 months of diagnosis.
2014-07-01 | E-MTAB-910 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) remains a cancer with dismal prognosis, particularly in high-risk disease patients and those ineligible for allogeneic stem cell transplantation. BCL-2 inhibitor venetoclax, in combination with hypomethylating agents, has emerged as an effective therapy and forms the backbone of multiple combination therapies in clinical trials. However, venetoclax-based therapy is rarely curative. While multiple venetoclax resistance mechanisms have been discovered, most of these have been identified using cell line models that only partially reflect the heterogeneous composition of human AML. Using paired single-cell data from 8 AML patients with pre- and post-venetoclax therapy samples, we aimed to characterize mechanisms driving venetoclax resistance in a clinically relevant setting.
2025-12-31 | E-MTAB-14143 | biostudies-arrayexpress