Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Co-targeting CDK4/6 and BRD4 promotes senescence and ferroptosis sensitivity in cancer

ABSTRACT: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors are approved for breast cancer treatment and show activity against other malignancies, including KRAS-mutant non-small cell lung cancer (NSCLC). However, the clinical efficacy of CDK4/6 inhibitors is limited due to frequent drug resistance and their largely cytostatic effects. Through a genome-wide cDNA screen, we identified that bromodomain-containing protein 4 (BRD4) overexpression conferred resistance to the CDK4/6 inhibitor palbociclib in KRAS-mutant NSCLC cells. Inhibition of BRD4, either by RNA interference or small-molecule inhibitors, synergized with palbociclib to induce senescence in NSCLC cells and tumors, and the combination prolonged survival in a KRAS-mutant NSCLC mouse model. Mechanistically, BRD4-inhibition enhanced cell cycle arrest and reactive oxygen species (ROS) accumulation, both of which are necessary for senescence induction; this in turn elevated GPX4, a peroxidase that suppresses ROS-triggered ferroptosis. Consequently, GPX4 inhibitor treatment selectively induced ferroptotic cell death in the senescent cancer cells, resulting in tumor regression. Co-targeting CDK4/6 and BRD4 also promoted senescence and ferroptosis vulnerability in pancreatic and breast cancer cells. Together, these findings reveal therapeutic vulnerabilities and effective combinations to enhance the clinical utility of CDK4/6 inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253204 | GEO | 2024/01/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Inhibition of GPX4 enhances CDK4/6 inhibitor activity in breast cancer.

Project description:CDK4/6 inhibition is the standard of care for estrogen receptor positive (ER+) breast cancer, although cytostasis is frequently observed, and new treatment strategies that enhance efficacy are required. We performed a genome-wide CRISPR screen to identify genetic determinants of CDK4/6 inhibitors sensitivity. Multiple genes involved in oxidative stress and ferroptosis modulated palbociclib sensitivity. Depletion or inhibition of GPX4 increased sensitivity to palbociclib in ER+ breast cancer models, and sensitised triple negative breast cancer models to palbociclib, with GPX4 null xenografts being highly sensitive to palbociclib. Palbociclib induced oxidative stress and disordered lipid metabolism with lipid peroxidation, leading to a ferroptosis-sensitive state. Lipid peroxidation relied on a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 inhibition creates vulnerability to ferroptosis that could be exploited through combination with GPX4 inhibitors, enhancing sensitivity to CDK4/6 inhibition in breast cancer.

2023-06-20 | PXD043133 | Pride

O-GlcNAcylation promotes Palbociclib resistance in breast cancer by regulating MITF nuclear translocation

Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remains an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we report that the Microphthalmia-associated transcription factor (MITF), was significantly elevated in palbociclib-resistance cells. Inhibition of MITF can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Mechanistically, we found that O-GlcNAc transferase (OGT) modifies MITF with O-GlcNAcylation at Serine 49 (Ser49) within its nuclear localization signal (NLS), thereby promoting MITF binding to importin α/ β and facilitating its nuclear transportation, which is crucial in regulating senescence.

2024-05-30 | PXD042838 | Pride

Stromal senescence following treatment with the CDK4/6 inhibitor palbociclib increases mammary cancer metastasis

Project description:One potential resistance mechanism to CDK4/6 inhibitors in breast cancer could be induction of cellular senescence in normal host tissues. The aim of our study was to identify CDK4/6 inhibition-induced changes to host tissues that impact metastasis. Using mouse models, we found that pre-treatment with palbociclib can increase metastatic seeding of mouse mammary cancer cells in the lungs and that this can be mitigated by eliminating senescent host cells. We describe palbociclib-induced gene expression changes in lungs that correlate with this effect and reveal altered intra-lung immune populations. Senescent endothelial cells are identifiable within lung metastases of mice pre-treated with palbociclib. Using in vitro models, we show that palbociclib treatment increases endothelial cell senescence and affects macrophage invasion and migration. These studies describe how CDK4/6 inhibition-induced cellular senescence in host tissues affects metastasis and disease progression in breast cancer, which remain key obstacles to achieving long-term survival.

2023-04-04 | GSE223759 | GEO

Proteomic characterisation of triple negative breast cancer cells following CDK4/6 inhibition

Project description:CDK4/6 inhibitor, Palbociclib, has shown a high success in breast cancer subtypes however it is often accompanied by a dependency on mutation status of cell lines. Consequently, there has been speculation on the breast cancer subtypes which should be offered treatment with specific CDK4/6 inhibitors and the response that can be expected. A common observation has been the induction of a cell programme known as "senescence" whereby cells experience a complete halt in mitosis, however, remaining metabolically active. Therapy-induced senescence markers and its effect on the tumour microenvironment as well as the diversity of this cell state remain unappreciated. In the following proteomics, phosphoproteomics and secretome datasets we focus on MDA-MB-231 cells, a triple negative cell line, to better understand the senescence-like cell state which arises after treatment. Ultimately, the dataset encompasses the population that arises upon Palbociclib treatment and highlights potential signatures and biomarkers of the cell state which could provide information on the use of CDK4/6 inhibitors in triple negative breast cancer subtypes.

2022-01-28 | PXD030407 | Pride

Tumor cell-specific Gpx4 deficiency reshaps tumor microenvironment and promotes NSCLC progression.

Project description:Knockout or inhibition of glutathione peroxidase 4 (GPX4) induces ferroptosis which has been proposed as a potential therapeutic strategy for cancer. Here we unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung cancer (NSCLC) progression in the autochthonous KrasLSL-G12D/+Lkb1fl/fl (KL) and KrasLSL-G12D/+Tp53fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells had an opposite effect. Mechanistically, knockout of GPX4 in tumor cells results in the accumulation of triacylglycerol (TAG) that was stored in lipid droplets in tumor cells and the efflux of TAG that induces ferroptosis of macrophages in the tumor microenvironment (TME), thereby igniting an immunoinhibitory TME characterized by the dysfunction of anti-tumor T cells and the decrease of antigen-presenting macrophages. Consistently, treatment with liprostatin-1 or inducible overexpression of GPX4 in tumor cells significantly rescues the ferroptosis of macrophages and ignites the activation of T cells in the TME, thereby inhibiting NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression by modulating TAG metabolism in the TME and provide potential therapeutic strategies for NSCLC.

2024-11-05 | GSE281159 | GEO

TRIB3 inhibition by palbociclib sensitizes prostate cancer to ferroptosis via SOX2-mediated SLC7A11 downregulation

Project description:Palbociclib is a CDK4/6 inhibitor approved for the treatment of breast cancer by suppressing cell proliferation. However, monotherapy with palbociclib was discouraging in prostate cancer, calling for a mechanism-based effective therapy. In this study, we reported in prostate cancer that palbociclib is a potent sensitizer of ferroptosis, which is worked out by downregulating the expression of TRIB3, a gene highly expressed in prostate cancer. Specifically, TRIB3 knockdown augmented the response of prostate cancer cells to ferroptosis inducers, whereas, TRIB3 overexpression rescued prostate cancer cells from palbociclib-induced ferroptosis. Mechanistically, TRIB3 inhibition by palbociclib resulted in downregulation of SOX2, which subsequently led to compromised expression of SLC7A11, a cystine/glutamate antiporter that counteracts ferroptosis. Functionally, a combined treatment of palbociclib with ferroptosis inducer significantly suppressed prostate cancer growth in a xenograft tumor model. Together, these results uncover an essential role of TRIB3/SOX2/SLC7A11 axis in palbociclib-induced ferroptosis, suggesting palbociclib a promising targeted therapy in combine with ferroptosis induction for the treatment of prostate cancer.

2024-10-31 | GSE273622 | GEO

RNA sequencing of luminal breast cancer patient-derived xenografts (PDX) library to capture tumor heterogeneity and explore the mechanisms of resistance to CDK4/6 inhibitors

Project description:Combining CDK4/6 inhibitors (CDK4/6i) with endocrine therapy has proven clinically effective and represents now the first-line treatment for advanced Luminal Breast Cancer (LBC) patients. However, resistance to CDK4/6i almost invariably arises in these patients, emphasising the critical need to comprehend these mechanisms and develop new strategies to overcome resistance. We report on the generation and characterisation of a LBC PDX displaying acquired resistance to CDK4/6i palbociclib. Treating a sensitive luminal BC PDX with the CDK4/6i palbociclib revealed that, despite initial tumour shrinkage, some tumours might eventually regrow under drug treatment. RNA sequencing, followed by gene set enrichment analyses, unveiled that this PDX have become refractory to CDK4/6i, both at biological and molecular level.

2024-11-18 | E-MTAB-14085 | biostudies-arrayexpress

Treatment of Retinoblastoma 1-Intact Hepatocellular Carcinoma With Cyclin-Dependent Kinase 4/6 Inhibitor Combination Therapy

Project description:Background and aims: Synthetic cyclin-dependent kinase (CDK) 4/6 inhibitors exert antitumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis, and increased immunogenicity. These agents currently have an indication in advanced breast cancers and are in clinical trials for many other solid tumors. HCC is one of promising targets of CDK4/6 inhibitors. RB family dysfunction is often associated with the initiation of HCC; however, this is revivable, as RB family members are not frequently mutated or deleted in this malignancy. Approach and results: Loss of all Rb family members in transformation related protein 53 (Trp53)-/- mouse liver resulted in liver tumor reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into multiple liver tumor cell lines induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an I kappa B kinase (IKK)β inhibitor Bay 11-7082. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/β phosphorylation and NF-κB activation. Combination therapy using palbociclib with Bay 11-7082 was significantly more effective in hepatoblastoma and HCC treatment than single administration. Moreover, blockade of IKK-NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact KRAS Kirsten rat sarcoma viral oncogene homolog mutated lung and colon cancers. Conclusions: In conclusion, CDK4/6 inhibitors have a potential to treat a wide variety of RB1-intact cancers including HCC when combined with an appropriate kinase inhibitor.

2021-05-26 | GSE153123 | GEO