RNA-seq of detecting the effect of CDK4&6 inhibitor Abemaciclib and VSV-M51 in glioma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE166914 | GEO | 2022/06/01
REPOSITORIES: GEO
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Project description:RNA-seq of detecting the effect of CDK4&6 inhibitor Abemaciclib and VSV-M51 in glioma
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Project description:We measured changes in gene expression in MCF7 with CDK4/6 and AP-1 inhibition by abemaciclib and SR11302, respectively.
2020-09-01 | GSE157214 | GEO
Project description:Resistance to CDK4/6 inhibitors plus endocrine therapy, standard of care for HR+/HER2-neg metastatic breast cancer (MBC) patients, remains as a clinical problem with limited therapeutic options after disease progression. Treatment with abemaciclib after progression on a prior CDK4/6i has received increasing interest. However, molecular predictors of cross-resistance and unique mechanism of resistance to each CDK4/6i are unknown. In this study, multiomics analyses revealed ≥30 differentially altered pathways between palbociclib and abemaciclib resistant models. Mechanistic, preclinical and retrospective clinical evidence showed that HR+/HER2-neg MBC tumors refractory to palbociclib still may be responsive to abemaciclib. Based on the unique mechanisms of resistance to each CDK4/6i, we propose that patients who would benefit from abemaciclib treatment post progression on palbociclib could be selected based on the Hallmark gene set enrichment of G2/M pathway, while those who most probably would be refractory could be identified base on the gene set enrichment of OXPHOS pathway.
2023-07-10 | GSE222367 | GEO
Project description:Resistance to CDK4/6 inhibitors plus endocrine therapy, standard of care for HR+/HER2-neg metastatic breast cancer (MBC) patients, remains as a clinical problem with limited therapeutic options after disease progression. Treatment with abemaciclib after progression on a prior CDK4/6i has received increasing interest. However, molecular predictors of cross-resistance and unique mechanism of resistance to each CDK4/6i are unknown. In this study, multiomics analyses revealed ≥30 differentially altered pathways between palbociclib and abemaciclib resistant models. Mechanistic, preclinical and retrospective clinical evidence showed that HR+/HER2-neg MBC tumors refractory to palbociclib still may be responsive to abemaciclib. Based on the unique mechanisms of resistance to each CDK4/6i, we propose that patients who would benefit from abemaciclib treatment post progression on palbociclib could be selected based on the Hallmark gene set enrichment of G2/M pathway, while those who most probably would be refractory could be identified base on the gene set enrichment of OXPHOS pathway.
2023-07-10 | GSE229146 | GEO
Project description:To investigate the role of combined PIN1 and CDK4 inhibition in the regulation of immune response, we performed RNA sequencing of TNBC tumors after treatment with Sulfopin, Abemaciclib or their combination
2024-03-08 | GSE232422 | GEO
Project description:Current research on CDK4/6 inhibitors (CDK4/6i) in the pre-clinical and clinical spaces are largely concerned with gaining a deeper understanding of how these drugs delay tumor growth, and how to prevent cancer cell resistance. By coordinating a first-in-kind phase II clinical trial of the CDK4/6i abemaciclib for patients with progressive dedifferentiated liposarcoma (DDLS) with cellular studies to identify the molecular basis of geroconversion, we have defined how therapy induced senescence contributes to disease management. Thirty patients with progressing DDLS enrolled in the clinical trial and were treated with 200mg abemaciclib twice daily. The median progression free survival was 33 weeks at the time of the data lock, with 23 of 30 progression-free at 12 weeks (76.7%, two-sided 95% CI 57.7% - 90.1%). ANGPTL4 is a necessary late regulator of geroconversion, the pathway from reversible cell cycle exit to a stably arrested inflammation-provoking senescent cell, in liposarcoma cell lines treated with CDK4/6i. Using ANGPTL4 and CDKN2A expression, we were able to identify patients in which abemaciclib induced tumor cell senescence. We were then able to correlate this with outcomes. Senesence correlated with increased leukocyte infiltration, primarily CD4-positive cells, within a month of therapy, and possibly with an improved initial response to abemaciclib. However, those individuals with both senescence and increased TILs were also more likely to acquire resistance after six months of therapy. This suggests that combining senolytics with abemaciclib in a subset of patients may improve the durability of patient responses to this class of compounds.
2023-08-21 | GSE241031 | GEO
Project description:The cellular and organismal phenotypic response to a small molecule kinase inhibitor is defined collectively by the inhibitor’s targets and their functions. The selectively of small molecule kinase inhibitors is commonly determined in vitro, using purified kinases and substrates. Recently, competitive chemical proteomics has emerged as a complementary, unbiased, cell-based approach to define the target landscape of kinase inhibitors. Here we evaluated and optimized a competitive multiplexed inhibitor bead mass spectrometry (MIB/MS) platform using cell lysates, live cells and treated mice. Several clinically active kinase inhibitors were profiled, including trametinib, BMS-777607, dasatinib, abemaciclib, and palbociclib. MIB/MS competition analyses of the cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors abemaciclib, and palbociclib revealed overlapping and unique kinase targets. Competitive MIB/MS analysis of abemaciclib revealed 83 target kinases, and dose-response profiling revealed glycogen synthase kinase 3 alpha and beta (GSK3 and GSK3 were the most potently inhibited. Cell based and in vitro kinase assays show that in contrast to palbociclib, abemaciclib directly inhibits (GSK3/β) kinase activity at low nanomolar concentrations. Consequently, abemaciclib activates β-catenin-dependent WNT signaling, as determined by β-catenin transcriptional activation and β-catenin protein stabilization. These data reveal differential kinase target specificities for CDK4/6 inhibitors may help explain differential clinical efficacy and dose-limiting toxicities. More broadly, we highlight the power of competitive chemical proteomics to identify multiple targets of kinase inhibitors in protein lysate, treated cells and in treated mice.
2017-12-07 | PXD006139 | Pride
Project description:To investigate the molecular mechanisms of resistance to ER downregulator and CDK4/6 inhibitors in ER+ breast cancer, we generated two cell lines, MCF7 and T47D, resistant to fulvestrant and abemaciclib after 6-8 months of exposure to increasing doses of the drug combination We performed gene expression profiling analysis using data obtained from RNA-seq of parental MCF7 or T47D and the respective fulvestrant and abemaciclib resistant cells
2023-06-05 | GSE227102 | GEO
Project description:Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omics approach to quantitatively profile kinome activation in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental Design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the effectivity of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor (LY3214996) alone and in combination to reduce PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust synergism of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor (LY3214996) in primary Nf1-/- Schwann cell cultures. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced anti-tumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusion: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
2023-06-26 | GSE213787 | GEO
Project description:Purpose: Plexiform neurofibromas (PNF) are peripheral nerve sheath tumors that cause significant morbidity in persons with neurofibromatosis type 1 (NF1), yet treatment options remain limited. To identify novel therapeutic targets for PNF, we applied an integrated multi-omics approach to quantitatively profile kinome activation in a mouse model that has predicted therapeutic responses in clinical trials for NF1-associated PNF with high fidelity. Experimental Design: Utilizing RNA sequencing combined with chemical proteomic profiling of the functionally enriched kinome using multiplexed inhibitor beads coupled with mass spectrometry, we identified molecular signatures predictive of response to CDK4/6 and RAS/MAPK pathway inhibition in PNF. Informed by these results, we evaluated the effectivity of the CDK4/6 inhibitor, abemaciclib, and the ERK1/2 inhibitor (LY3214996) alone and in combination to reduce PNF tumor burden in Nf1flox/flox;PostnCre mice. Results: Converging signatures of CDK4/6 and RAS/MAPK pathway activation were identified within the transcriptome and kinome that were conserved in both murine and human PNF. We observed robust synergism of the CDK4/6 inhibitor, abemaciclib, in combination with the ERK1/2 inhibitor (LY3214996) in primary Nf1-/- Schwann cell cultures. Consistent with these findings, the combination of abemaciclib (CDK4/6i) and LY3214996 (ERK1/2i) synergized to suppress molecular signatures of MAPK activation and exhibited enhanced anti-tumor activity in Nf1flox/flox;PostnCre mice in vivo. Conclusion: These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.
2023-06-26 | GSE213786 | GEO