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.
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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:Biomarker studies for cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) are often limited by tissue availability and narrow genomic assessments. We conducted a multicenter prospective study to obtain an unbiased 'omics’ assessment of tumors derived from women commencing 1st line (1L) palbociclib plus letrozole for HR+ HER2- MBC. We generated RNA and DNA data from baseline and a subset of progression samples. Patient-derived xenograft models were established from 10 samples. Genome-wide analyses and semi-supervised assessments of RB1-genes were conducted using whole exome and RNA sequencing data from baseline and progression tumors. Genes (FAT1, MYC, CDK2, and AMBRA1) known to drive CDK4/6i response, were confirmed to be associated with progression free survival (PFS). Novel CDK4/6i response genes including TIMELESS, SAE1, CENPU, SPAG5, and EXO1, as well as copy alterations in cytobands 12q21.2; 11q24.2; 1p22.3; 11p15.1, and 4q22.2 were observed to be associated with PFS. Paired baseline/progression samples demonstrated enrichment of genes involved in lipid metabolic processes, particularly beta oxidation as well as frequent intrinsic subtype switching. An RB1 signature, associated with shorter PFS (HR=2.72, p=0.006) and lack of cell cycle arrest in the NeoPalana study, may identify a subgroup of patients with de novo endocrine resistance.
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Project description:HR+HER2- breast cancers resistant to palbociclib-hormone therapy displayed increased lipid uptake and expression of stress response proteins (GPX4, PSMA7), by adding ferroptosis inducers to palbocilib-fulvestrant combination therapy, tumor response was enhanced in three different pre-clinical models: resistant cells, xenografts and PDX.
2025-01-06 | GSE270021 | GEO
Project description:Biomarker studies for cyclin-dependent 4/6 kinase inhibitors (CDK4/6i) are often limited by tissue availability and narrow genomic assessments. We conducted a multicenter prospective study to obtain an unbiased 'omics’ assessment of tumors derived from women commencing 1st line (1L) palbociclib plus letrozole for HR+ HER2- MBC. We generated RNA and DNA data from baseline and a subset of progression samples. Patient-derived xenograft models were established from 10 samples. Genome-wide analyses and semi-supervised assessments of RB1-genes were conducted using whole exome and RNA sequencing data from baseline and progression tumors. Genes (FAT1, MYC, CDK2, and AMBRA1) known to drive CDK4/6i response, were confirmed to be associated with progression free survival (PFS). Novel CDK4/6i response genes including TIMELESS, SAE1, CENPU, SPAG5, and EXO1, as well as copy alterations in cytobands 12q21.2; 11q24.2; 1p22.3; 11p15.1, and 4q22.2 were observed to be associated with PFS. Paired baseline/progression samples demonstrated enrichment of genes involved in lipid metabolic processes, particularly beta oxidation as well as frequent intrinsic subtype switching. An RB1 signature, associated with shorter PFS (HR=2.72, p=0.006) and lack of cell cycle arrest in the NeoPalana study, may identify a subgroup of patients with de novo endocrine resistance.
2026-01-28 | GSE317628 | 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:Metastatic HR+ HER2- breast cancer is an intractable disease that resists to the first-line treatment based on the combination of CDK4/6 inhibitor and hormone therapy (HT). To identify targets that further increase palbociclib-HT efficacy, we utilized biopsies from cancer patients who showed recurrence after treatment, HR+HER2- luminal cancer cells sensitive and resistant to the palbociclib-HT. Proteomic analysis of human samples revealed an upregulation of the oxidative stress-triggered proteasome subunit alpha7 (PSMA7) in metastatic relapses in different organs after patient's resistance to palbociclib-HT combination.
2025-05-07 | PXD053296 | Pride
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: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.
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