D8a9f2c4-e5da-40db-acea-ecdbf78c5a1d - samples
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ABSTRACT:
PROVIDER: EGAD00001009068 | EGA |
REPOSITORIES: EGA
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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
Project description:Targeted sequencing analyses was made on samples of PDX engrafted with breast cancer bone metastases, 2 PDX acquired resistance to palbociclib.
| EGAD00001006070 | EGA
Project description:Resistance to endocrine treatments and CDK4/6 inhibitors is considered a near-inevitability in most patients with estrogen receptor positive breast cancers (ER + BC). By genomic and metabolomics analyses of patients' tumours, metastasis-derived patient-derived xenografts (PDX) and isogenic cell lines we demonstrate that a fraction of metastatic ER + BC is highly reliant on oxidative phosphorylation (OXPHOS). Treatment by the OXPHOS inhibitor IACS-010759 strongly inhibits tumour growth in multiple endocrine and palbociclib resistant PDX. Mutations in the PIK3CA/AKT1 genes are significantly associated with response to IACS-010759. At the metabolic level, in vivo response to IACS-010759 is associated with decreased levels of metabolites of the glutathione, glycogen and pentose phosphate pathways in treated tumours. In vitro, endocrine and palbociclib resistant cells show increased OXPHOS dependency and increased ROS levels upon IACS-010759 treatment. Finally, in ER + BC patients, high expression of OXPHOS associated genes predict poor prognosis. In conclusion, these results identify OXPHOS as a promising target for treatment resistant ER + BC patients.
2023-06-27 | MTBLS3342 | MetaboLights
Project description:A significant proportion of patients with oestrogen receptor (ER) positive breast cancers (BC) develop resistance to endocrine treatments (ET) and relapse with metastatic disease. Bone is the most common metastatic site in ER+ patients, however bone metastases are technically challenging to biopsy and analyse. Difficulties concern both tumour tissue acquisition and techniques for analysis and RNA extractions. Patient-derived xenografts (PDX) of BC bone metastases have not been reported yet. For the first time we established PDX models from bone metastatic biopsies of patients progressing on ET and treated by vertebroplasty. PDX models were analysed at transcriptomic level and compared to patient’s early primary tumours to identify new therapeutic targets associated with endocrine resistance in the metastatic setting. Identification of activated signalling pathways in bone metastasis by comparative transcriptomic analyses of the bone metastasis derived PDX compared to the patients' primary breast tumor.
2020-06-29 | GSE146661 | GEO
Project description:A significant proportion of patients with oestrogen receptor (ER) positive breast cancers (BC) develop resistance to endocrine treatments (ET) and relapse with metastatic disease. Bone is the most common metastatic site in ER+ patients, however bone metastases are technically challenging to biopsy and analyse. Difficulties concern both tumour tissue acquisition and techniques for analysis and RNA extractions. Patient-derived xenografts (PDX) of BC bone metastases have not been reported yet. For the first time we established PDX models from bone metastatic biopsies of patients progressing on ET and treated by vertebroplasty. PDX models were analysed at genomic level to identify new therapeutic targets associated with endocrine resistance in the metastatic setting. Identification of chromosomic alterations in bone metastasis derived PDX.
2020-06-29 | GSE149038 | 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.
2020-04-29 | PXD005514 | Pride
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
Project description:Endocrine therapies (ET) combined with CDK4/6 inhibition (CDK4/6i) is standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however lethal drug resistance is common. Proteogenomic analyses of 22 ER+ breast cancer patient-derived xenografts (PDXs) demonstrated that PKMYT1, a WEE1 homolog, is highly estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2 independent. In clinical samples, high PKMYT1 mRNA is a resistance biomarker for both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib(RP-6306) and gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53 in vitro; the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. These results demonstrate the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6i resistant TP53 mutant ER+ breast cancer.
2025-05-13 | PXD050619 | Pride
Project description:Identify mecanisms of metastatic breast cancer resistance to palbociclib by RNAseq analyses.
| EGAS00001006428 | EGA
Project description:Therapeutic resistance in cancer results from genetic or epigenetic mechanisms that enable cell survival under drug pressure. While several resistance mechanisms to cyclin-dependent kinase inhibitors have been identified, acquired resistance is still a therapeutic challenge. Here, we have systematically analyzed metabolic reprogramming in colorectal cancer cells exposed to Palbociclib, a CDK4/6 inhibitor, or Telaglenestat, a glutaminase inhibitor. Through multiple approaches, we show that Palbociclib and Telaglenestat elicit complementary metabolic responses and are thus uniquely suited to counter the metabolic reprogramming induced by the reciprocal drug. As such, while Palbociclib induced reduced tumor growth in vivo, and Telaglenestat did not show a significant effect, the drug combination displayed a strong synergistic effect on tumor growth. Likewise, initial responses to Palbociclib were followed by signs of adaptation and resistance, which were prevented by combining Palbociclib with Telaglenestat. The combination of Palbociclib and Telaglenestat may effectively forestall acquired resistance to Palbociclib.
2025-07-22 | GSE245085 | GEO