Longitudinal Mult-omics Study of Palbociclib Resistance in Hormone Receptor (HR) Positive/Human Epidermal Growth Factor Receptor (HER) 2 Negative Metastatic Breast Cancer (MBC)
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PROVIDER: PRJNA776728 | ENA |
REPOSITORIES: ENA
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Project description:A comprehensive genomic and transcriptomic analysis of pre-treatment and post-treatment tumors from Asian metastatic breast cancer patients treated with palbociclib plus endocrine therapy identified novel markers associated with poor prognosis.
2023-05-09 | GSE186901 | 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: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:Introduction In HR+/HER2- metastatic breast cancer (MBC) is imperative to identify patients who respond poorly to CDK4/6i and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting but further validation is needed. Methods We performed mRNA gene expression profiling and correlation with progression-free-survival (PFS) on 455 tumor samples included in the phase III PEARL study, that assigned HR+/HER2- MBC patients to receive palbociclib+ET vs capecitabine. ER+/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET. Results Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4months (m) with palbociclib+ET and 9.3m with capecitabine; HR:4.16, adjusted p-value<0.0001. Tumors with high CCNE1 expression (above median) had also worse median PFS with palbociclib+ET (6.2m) than with capecitabine (9.3m); HR:1.55, adjusted p-value=0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile) we found higher levels of Polo Like Kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models we show that PLK1 inhibition reverses resistance to palbociclib+ET. Conclusion We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.
2023-01-26 | GSE223700 | GEO
Project description:Purpose: We wanted to explore further heterogeneity of MBC subsets that were previously defined by our lab. Methods: MBC subsets were sorted and stained with unique anti-mouse HTO antibodies (CITE-seq). Results: We found that heterogeneity among MBC subsets was most prominent among DP MBC subsets, which could be separated by extrafollicular or germinal center transcriptional signatures, whereas DN and SP MBCs mostly exhibited an extrafollicular signature.
2024-01-07 | GSE225673 | GEO
Project description:Over the last decade, CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have emerged as promising anticancer drugs. Numerous studies have demonstrated that CDK4/6 inhibitors efficiently block the pRb-E2F pathway and induce cell cycle arrest in pRb-proficient cells. Based on these studies, the inhibitors have been approved by the FDA for treatment of advanced hormonal receptor (HR) positive breast cancers in combination with hormonal therapy. However, some evidence has recently shown unexpected effects of the inhibitors, promoting needs to understand more about the mechanism of inhibitors beyond pRb. Our study demonstrates here for the first time how palbociclib impairs the origin firing in the DNA replication process in pRb-deficient cell lines. Strikingly, despite the absence of pRb, cells treated with palbociclib synthesize less DNA without any induced cell cycle arrest. Furthermore, palbociclib treatment disturbs the temporal program of DNA replication and reduces the density of replication forks. Cells treated with palbociclib show a defect in the loading of proteins of the Pre-initiation complex (Pre-IC) on chromatin, indicating a reduced initiation of DNA replication. Our findings highlight hidden effects of palbociclib on the dynamics of DNA replication and on its cytotoxic consequences on cell viability in the absence of pRb. This study provides a potential therapeutic application of palbociclib to target genomic instability towards pRb deficient patient
2023-07-01 | GSE180530 | 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:RNA-seq was performed to compare the transcriptional programmes of palbociclib-resistant A375 and CHL1 cells compared to their parental counterparts Cyclin dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor positive breast cancer and are currently in clinical development in melanoma; a tumour that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib, and demonstrated that palbociclib-mediated inhibition of PRMT5 is essential for sensitivity to CDK4/6 inhibitors. Mechanistically, by inhibiting PRMT5 activity, palbociclib alters MDM4 pre-mRNA splicing leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 increases p21 leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treatment naïve and resistant models and also delays the emergence of resistance. Our studies have uncovered a novel mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide pre-clinical evidence that co-inhibition of CDK4/6 and PRMT5 is an effective and well tolerated therapeutic strategy. Overall our data provides a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors in not only melanoma but other tumour types including breast, pancreatic and esophageal carcinoma.
2019-08-23 | GSE133567 | GEO
Project description:Resistance to CDK4/6 inhibitors and endocrine therapy (ET) are common and poorly understood since they have been real game changer in patients with HR-positive and HER2-negative MBC. A comprehensive genomic and transcriptomic analysis of pre-treatment and post-treatment tumors from patients treated with palbociclib plus ET identified novel markers associated with poor prognosis such as genomic scar features caused by homologous repair deficiency (HRD), estrogen response signatures, and four unique prognostic clusters with distinct molecular features. Tumors with TP53 mutations co-occurring with a unique HRD-high cluster responded poorly. By comparing genomic and transciptomic profiles of paired samples, tumors were found to be further enriched in HRD genomic scars and many had switched to aggressive molecular subtypes. Furthermore, we identified high frequencies of acquired genomic alterations upon disease progression in RB1, ESR1, PTEN, and KMT2C. Our findings provide new insight into potential predictive biomarkers that could be targeted to overcome resistance. (NCT03401359)
| EGAS00001005736 | EGA
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