Multi-omics analysis of the breast cancer response to palbociclib
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ABSTRACT:
PROVIDER: PRJNA1266961 | ENA |
REPOSITORIES: ENA
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Project description:The addition of CDK4/6 inhibitors to endocrine therapy has significantly improved outcomes in HR+/HER2- breast cancer. However, variable patient responses and acquired resistance remain a clinical challenge. We therefore defined the comprehensive molecular response to palbociclib, the most clinically used CDK4/6 inhibitor. Global analyses of gene expression, protein abundance, splicing, and chromatin accessibility revealed broad patterns and specific changes that result from CDK4/6-inhibition in breast cancer cells. We uncovered unexpected feedback between CDK4/6 and estrogen-response signaling, which has clear clinical implications. We also revealed a widespread alternative splicing program that partially overlapped with genes whose expression is regulated, and which is expected to impact protein function. These molecular changes nominated combination therapies that interfere with the activation of CDKs or ERα. Accordingly, co-targeting CDK7, which regulates CDK2, CDK4/6 and ERα, additively impacted cell fitness. Collectively, these data reveal a complex, multi-tiered response to CDK4/6 inhibition, with implications for therapeutic efficacy.
2025-11-04 | GSE297939 | GEO
Project description:While targeted therapies directed against cancer cells have proven effective, their clinical benefit is often limited by acquired resistance. This clinical challenge underscores the importance of uncovering the molecular mechanisms behind resistance in order to develop novel targets and drug combinations that can stop the growth of cancer cells. Two pivotal pathways controlling tumor growth are glucose metabolism and cell cycle. PFKFB3 and CDK4/6 are key regulators of glucose metabolism and cell cycle respectively for which inhibitors have been developed. PFK158 is an inhibitor against PFKFB3 that is currently undergoing phase I clinical trials and has shown to be effective at blocking glucose metabolism in solid tumors. Palbociclib, a novel CDK4/6 inhibitor was recently approved as a first-line approach for the treatment of estrogen receptor (ER) positive breast cancer because of the very promising clinical responses in ER+ breast cancer patients. Unfortunately, the effects of these therapies are short-lasting since cancer cells ultimately develop resistance allowing them to escape treatment. To identify the molecular mechanisms driving resistance to PFK158 or palbociclib, we have generated ER+ MCF7 and ER- MDA-MB231 cells resistant to either PFK158 or palbociclib by continuous exposure to increasing doses of drugs for a period of three months. Our hypothesis is that resistance is driven by activating mutations and/or pathways acquired during the course of treatment. This study is designed to identify specific mutations and/or changes in gene expression responsible for the resistance to PFK158 or palbociclib in ER+ and ER- in vitro. The results of this study will lead to the development of new therapeutic strategies to overcome resistance to PFKFB3 and CDK4/6 inhibitors.
2019-06-20 | GSE130437 | GEO
Project description:Estrogen receptor positive (ER+) breast cancers are the most common type of breast cancer. Despite the great efficacy of endocrine therapies, resistance remains a problem. Therefore, there is an immediate need for new, effective therapies in ER+ BC. In this study, we have explored the role of a potent CDK4/6 inhibitor called palbociclib. In order to identify differential phosphoproteomic events that underpin the mode of action and recurrence for this treatment, we generated a panel of palbociclib-sensitive and resistant cell lines and did quantitative, shotgun phosphoproteomics using titanium IMAC. Palbociclib sensitive cell lines (wt-MCF7 or MCF7-LTED) were cultured in phenol red-free RPMI supplemented with 10% FBS and 1nM estradiol or 10% dextran-coated charcoal (DCC) respectively. Thereafter, palbociclib resistant cell lines were generated using 1μΜ palbociclib concentration. Samples were harvested at baseline and at the point of resistance.
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Project description:Combined inhibition of STAT3 and DNA repair in palbociclib-resistant ER-positive breast cancer
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Project description:Cytoplasmic pattern recognition receptors (PRRs) for double-stranded RNA (RIG-I/MDA5) are key mediators of anti-viral responses. PRR agonists, such as dsRNA oncolytic Reovirus type 3 Dearing (Rt3D), potently activate RNA sensors. We used an unbiased cytotoxicity screen to reveal synergistic drug-virotherapy combinations and found potent effects of Rt3D combined with the CDK4/6 inhibitor, palbociclib. The combination augmented oncolytic virus-induced endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and the expression and activation/signaling of RNA sensors. Combined Rt3D-palbociclib treatment potently increased interferon production and signaling, and knockdown studies implicated key UPR proteins and the RNA sensor, RIG-I, as essential to the phenotype observed. Further experiments, using canonical RIG-I agonists and an ER stress inducer, thapsigargin, confirmed cross-talk between RNA sensing and ER stress pathways that augmented cancer cell death and interferon production. Combined Rt3D-palbociclib also increased innate immune activation within tumour cells and IFN-induced HLA expression. Analysis of the immunopeptidome revealed changes to HLA-captured peptides with Rt3D-palbociclib, including altered expression of peptides from cancer/testis antigens (CTA) and endogenous retroviral elements (ERVs). Our findings highlight cross-talk between UPR signaling and RNA-mediated PRR activation as a means of enhancing anti-cancer efficacy with potential pro-immunogenic consequences. This has implications for future clinical development of PRR agonists and oncolytic viruses, and broadens the therapeutic remit of CDK4/6 inhibitors to include roles as both ER stress and dsRNA PRR sensitizers.
2025-05-02 | PXD036559 | Pride
Project description:Cytoplasmic pattern recognition receptors (PRRs) for double-stranded RNA (RIG-I/MDA5) are key mediators of anti-viral responses. PRR agonists, such as dsRNA oncolytic Reovirus type 3 Dearing (Rt3D), potently activate RNA sensors. We used an unbiased cytotoxicity screen to reveal synergistic drug-virotherapy combinations and found potent effects of Rt3D combined with the CDK4/6 inhibitor, palbociclib. The combination augmented oncolytic virus-induced endoplasmic reticulum (ER) stress/unfolded protein response (UPR) and the expression and activation/signaling of RNA sensors. Combined Rt3D-palbociclib treatment potently increased interferon production and signaling, and knockdown studies implicated key UPR proteins and the RNA sensor, RIG-I, as essential to the phenotype observed. Further experiments, using canonical RIG-I agonists and an ER stress inducer, thapsigargin, confirmed cross-talk between RNA sensing and ER stress pathways that augmented cancer cell death and interferon production. Combined Rt3D-palbociclib also increased innate immune activation within tumour cells and IFN-induced HLA expression. Analysis of the immunopeptidome revealed changes to HLA-captured peptides with Rt3D-palbociclib, including altered expression of peptides from cancer/testis antigens (CTA) and endogenous retroviral elements (ERVs). Our findings highlight cross-talk between UPR signaling and RNA-mediated PRR activation as a means of enhancing anti-cancer efficacy with potential pro-immunogenic consequences. This has implications for future clinical development of PRR agonists and oncolytic viruses, and broadens the therapeutic remit of CDK4/6 inhibitors to include roles as both ER stress and dsRNA PRR sensitizers.
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Project description:The goal of this study is to measure gene expression changes resulting over time of palbociclib treatment of T47D, MCF7, and CAMA1 ER+ breast cancer cell lines.
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Project description:The results from our study have identified two clinically relevant, divergent and druggable pathways (DNA repair and STAT3) that can be targeted in combination to effectively combat drug resistance. We also found that the same pathways that were deregulated in palbociclib-resistant cells were also altered in tumor samples obtained from patients who progressed while on palbociclib and endocrine therapy
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Project description:To understand how Palbociclib (a CDK4/6 inhibitor) treatment changes the transcriptome of hematopoietic stem and progenitor cells, wildtype cells were isolated from mice and treated for 24h with either PBS (control) or Palbociclib. After 24h of culture, the cell suspensions were collected and sorted for lineage-negative, Sca1-positive, cKit-positive (LSK) cells which were subjected to library prep for single cell RNA sequencing.
2024-05-22 | E-MTAB-13268 | biostudies-arrayexpress
Project description:Estrogen receptor positive (ER+) breast cancer is the most common type of breast cancer. Despite the great efficacy of endocrine therapies, resistance remains a problem. Therefore, there is an immediate need for new, effective therapies in ER+ BC. In this study, we have explored the role of a potent CDK4/6 inhibitor called palbociclib. In order to identify alterations in protein abundance between the responsive and resistant setting, we generated a panel of palbociclib-sensitive and resistant cell lines and did quantitative, shotgun proteomics using dimethyl labelling. Palbociclib sensitive cell lines (wt-MCF7 or MCF7-LTED) were cultured in phenol red-free RPMI supplemented with 10% FBS and 1nM estradiol or 10% dextran-coated charcoal (DCC) respectively. Thereafter, palbociclib resistant cell lines were generated using 1μΜ palbociclib concentration. Samples were harvested at baseline and at the point of resistance.
2020-03-25 | PXD005611 | Pride