Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CDK4/6 Inhibition reprograms the Breast Cancer immunopeptidome via Rb-Dependent chromatin and transcriptomic remodeling

ABSTRACT: The Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are standard-of-care therapies for metastatic hormone receptor-positive (HR+) breast cancer, yet their immunomodulatory effects remain underexplored. Here, we demonstrate that CDK4/6 inhibition with Abemaciclib reprograms the tumor antigen landscape by increasing MHC-I presentation and reshaping the immunopeptidome in HR+ and triple-negative breast cancer (TNBC) cells. Through multiomics integration, we reveal that this remodeling is driven by retinoblastoma protein (Rb)-dependent transcriptional and chromatin reprogramming, reflected by increased H3K27ac deposition and enhanced chromatin accessibility revealed by ATAC-seq. CDK4/6 inhibition dephosphorylates Rb, enhancing its interaction with BET family proteins and inducing chromatin remodeling that upregulates antigen-source transcripts. We identify immunogenic Abemaciclib-induced MHC-I peptides, including antigens derived from non-coding genomic regions, which can enhance tumor immunogenicity. These findings reveal a previously unrecognized role of CDK4/6is in shaping tumor antigenicity and suggest that combining CDK4/6is with immunotherapy could broaden antigenic targets in breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE304997 | GEO | 2025/11/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

CDK4/6 Inhibition reprograms the Breast Cancer immunopeptidome via Rb-Dependent chromatin and transcriptomic remodeling

Project description:The Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) are standard-of-care therapies for metastatic hormone receptor-positive (HR+) breast cancer, yet their immunomodulatory effects remain underexplored. Here, we demonstrate that CDK4/6 inhibition with Abemaciclib reprograms the tumor antigen landscape by increasing MHC-I presentation and reshaping the immunopeptidome in HR+ and triple-negative breast cancer (TNBC) cells. Through multiomics integration, we reveal that this remodeling is driven by retinoblastoma protein (Rb)-dependent transcriptional and chromatin reprogramming, reflected by increased H3K27ac deposition and enhanced chromatin accessibility revealed by ATAC-seq. CDK4/6 inhibition dephosphorylates Rb, enhancing its interaction with BET family proteins and inducing chromatin remodeling that upregulates antigen-source transcripts. We identify novel Abemaciclib-induced MHC-I peptides, including antigens derived from non-coding genomic regions, which can enhance tumor immunogenicity. These findings reveal a previously unrecognized role of CDK4/6is in shaping tumor antigenicity and suggest that combining CDK4/6is with immunotherapy could broaden antigenic targets in breast cancer.

2025-11-12 | GSE287955 | GEO

Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Late Progression to CDK4/6 Inhibition in Patients with HR+/HER2- Metastatic Breast Cancer [FFPE]

Project description:This study addresses the critical need for predictive biomarkers in patients with hormone receptor–positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) who have been treated with cyclin-dependent kinase 4/6 inhibitors (CDK4/6is). Using single-cell RNA sequencing, we reveal differential mechanisms of early versus late progression, enhancing our understanding of resistance to CDK4/6is. We identify and validate tumor-specific molecular biomarkers and demonstrate that tumor-infiltrating cytotoxic natural killer and CD8+ T cells are predictive of therapeutic response. Additionally, increased immune activity suppression in late progressing tumors suggests that combining CDK4/6is with checkpoint inhibitors could be beneficial against drug resistance. Validation across 2 independent cohorts confirms the robustness and clinical relevance of our findings. These insights pave the way for optimizing therapeutic strategies based on microenvironment-specific changes, offering a personalized and effective approach to managing HR+/HER2- mBC and improving patient outcomes.

2025-02-18 | GSE274141 | GEO

Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Late Progression to CDK4/6 Inhibition in Patients with HR+/HER2- Metastatic Breast Cancer [tissue]

2025-02-18 | GSE274139 | GEO

Efficacy of abemaciclib in palbociclib-resistant hormone receptor positive organoids derived from patient derived xenografts from patients who progressed on palbociclib

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

Efficacy of abemaciclib in palbociclib-resistant hormone receptor positive breast cancer cell lines: MCF-7 and T47D

2023-07-10 | GSE222367 | GEO

BLU-222, a Potent CDK2 Inhibitor, Synergizes with CDK4/6 Inhibitors to Overcome Drug Resistance in HR–Positive and Triple-Negative Breast Cancer by Inducing p21 and p27

Project description:Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) combined with endocrine therapy are the standard first-line treatment for hormone receptor-positive, HER2−negative (HR+/HER2−) metastatic breast cancer, but resistance develops over time. In triple-negative breast cancer (TNBC), the efficacy of CDK4/6i is unclear. Our study shows that the selective CDK2 inhibitor BLU-222, while effective alone, enhances synergistic activity when combined with CDK4/6i in resistant HR+/HER2− and TNBC models, leading to increased apoptosis and cell cycle arrest. In vivo, combining BLU-222 with palbociclib or ribociclib showed significant antitumor effects across 8 models, resulting in durable tumor regression and extended survival. Mechanistically, BLU-222, alone or with palbociclib, upregulated p21 and p27 expression and enhanced p21 binding to CDK2 as well as p21 and p27 binding to CDK4 complexes. CRISPR knockout of p21 or p27 in palbociclib-resistant cells eliminated this synergy. Further, RNA sequencing showed that the combination treatment upregulated senescence and interferon pathways, offering insights into the observed therapeutic synergy.

2025-11-18 | GSE282705 | GEO

Therapeutic benefits of maintaining CDK4/6 inhibitors and incorporating CDK2 inhibitors beyond progression in breast cancer

Project description:The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) has significantly improved outcomes for patients with hormone receptor-positive (HR+) metastatic breast cancer. However, most patients eventually develop resistance, leading to treatment discontinuation. The therapeutic benefits of maintaining CDK4/6i or transitioning to CDK2 inhibitors (CDK2i) beyond disease progression remain unclear. Here, we show that maintaining CDK4/6i and ET or combining them with CDK2i effectively suppresses the growth of drug-resistant HR+ breast cancer cells by prolonging G1-phase progression. CDK4/6i maintenance triggers a non-canonical pathway for Rb inactivation through post-translational degradation, resulting in attenuated E2F activity and slowed G1 progression. ET further augments this effect by inhibiting c-Myc-mediated E2F amplification. Although the maintenance of CDK4/6i and ET outperforms CDK2i with ET, the triple combination of CDK4/6i, CDK2i, and ET most effectively suppresses both E2F activity and tumor growth. Moreover, while overexpression of both cyclin E and A can promote resistance to the CDK4/6i and CDK2i combination, cyclin E plays a more pivotal role in developing resistance. These findings highlight the potential of sustained CDK4/6i therapy and the incorporation of CDK2i to mitigate resistance in HR+ breast cancer.

2024-10-10 | GSE279160 | GEO

Rb and the APC/C coactivator FZR1 determine CDK4/6-Cyclin D requirement in C. elegans and human cancer cells

Project description:Cyclin dependent kinase 4 and 6 (CDK4/6) in complex with D-type cyclins promote cell cycle entry, at least in part through phosphorylation of the retinoblastoma tumor suppressor protein (Rb). The CDK4/6-cyclin D-Rb pathway is commonly deregulated in human cancer, often through CDK4/6 or D-type cyclin overexpression, or inactivation of the CDK4/6 antagonist p16/CDKN2A. Importantly, a substantial fraction of cancers depend on continuous CDK4/6-cyclin D kinase activity and are sensitive to CDK4/6-specific inhibitors. Here, we investigate critical CDK4/6-cyclin D functions that may determine the sensitivity to CDK4/6 inhibitors, making use of the essential roles of CDK4/6 (CDK-4) and cyclin D (CYD-1) in the nematode C. elegans. In an unbiased screen, we found that simultaneous loss of C. elegans Rb (lin-35) and down-regulation of the APC/C substrate specificity factor FZR1/Cdh1 completely overcomes CDK-4/CYD-1 requirement. Furthermore, CDK-4/CYD-1 phosphorylates specific residues in the LIN-35 Rb spacer domain and FZR-1 N-terminus that correspond to inactivating phosphorylations of the human homologs. Thus, CDK-4/CYD-1 appears to promote cell cycle entry by antagonizing not only transcriptional repression by LIN-35 Rb but also protein degradation by APC/CFZR-1. Simultaneous knockdown of Rb and FZR1 in human breast cancer cells synergistically overcomes arrest by the CDK4/6-specific inhibitor PD 00332991. These results reveal APC/CFZR1 as a putative CDK4/6-Cyclin D target and important contributing factor in the response to CDK4/6-inhibitor treatment.

2016-07-05 | PXD001501 | Pride

CDK4/6 inhibitors modulate the ubiquitin proteosomal pathway by suppression of the ubiquitin conjugating enzymes UBE2C/S/T

Project description:Despite significant improvement in therapeutic development in the past decades, breast cancer remains a formidable cause of death for women worldwide. The hormone positive subtype (HR(+)) (also known as luminal type) is the most prevalant category of breast cancer, comprising ~70% of patients. The clinical success of the three CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib has revolutionzied the treatment of choice for metastatic HR(+) breast cancer. Accumulating evidence demonstrate that the properties of CDK4/6 inhibitors extend beyond inhibition of the cell cycle, including modulation of immune function , sensitizing PI3K inhibitors, metabolism reprogramming , kinome rewiring, modulation of the proteosome, and many others. The ubiquitin–proteasome pathway (UPP) is a crucial cellular proteolytic system that maintains the homeostasis and turnover of proteins. By transcriptional profiling of the HR(+) breast cancer cell lines treated with the three CDK4/6 inhibitors, we have uncovered a novel mechanism that demonstrate the CDK4/6 inhibitors suppress the expression of three ubiquitin conjugating enzymes UBE2C, UBE2S, UBE2T. These three E2 enzymes modulate a number of E3 ubiquitin ligases, including the APC/C complex which plays a role in G1/S progression. Our study provide a novel link between CDK4/6 inhibitor and UPP which could have important implications in cancer biology.

2022-04-23 | GSE201113 | GEO

RB-loss determines selective resistance and novel vulnerabilities in breast cancer modelsRB loss

Project description:The retinoblastoma tumor suppressor (RB1) plays a critical role in coordinating multiple pathways that impact on tumor initiation, disease progression, and therapeutic responses. Here we interrogated the effect of CDK4/6 inhibitor in combination with mTOR inhibtor. Also, we interrogtaed the efffect of AURK and WEE1 inhibition in ER+ breast cacner models While the RB-pathway has been purported to exhibit multiple mutually exclusive events, only RB1 is mutually exclusive with multiple genetic events that deregulate CDK4/6 activity. Using an isogenic ER+ breast cancer model with targeted RB1 deletion, we identified gene expression features that link CDK4/6 activity and RB-dependency (CDK4/6-RB integrated signature). We also investigated the role of RB on apoptotic pathway. Single copy loss on chromosome 13q encompassing the RB1 locus is prevalent in many cancers, and is associated with reduced expression of multiple genes on 13q including RB1, and inversely related to the CDK4/6-RB integrated signature supporting a genetic cause/effect relationship. To probe the broader implications on tumor biology, we investigated genes that are positively and inversely correlated with the CDK4/6-RB integrated signature. This approach defined tumor-specific pathways that could represent new therapeutic vulnerabilities associated with RB-pathway activity.

2021-08-31 | GSE182631 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data