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RUNX1-PDGFBB-AKT pathway mediated CDK4/6 inhibitor resistance in HR+/HER2- breast cancer

ABSTRACT: RUNX1-PDGFBB-AKT pathway mediated CDK4/6 inhibitor resistance in HR+/HER2- breast cancer

PROVIDER: PRJNA1101560 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28726540_1.fastq.gz	Fastqsanger.gz
	SRR28726540_2.fastq.gz	Fastqsanger.gz
	SRR28726541_1.fastq.gz	Fastqsanger.gz
	SRR28726541_2.fastq.gz	Fastqsanger.gz
	SRR28726542_1.fastq.gz	Fastqsanger.gz

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RUNX1-PDGFBB-AKT pathway mediated CDK4/6 inhibitor resistance in HR+/HER2- breast cancer

Project description:Cyclin-dependent kinases 4 and 6 (CDK4/6) are essential drivers of the cell cycle and are also critical for the initiation and progression of diverse malignancies. Pharmacological inhibitors targeting CDK4/6 have demonstrated significant activity against various tumor types such as breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i) (such as palbociclib) remain an immense obstacle in clinical and the underlying mechanisms have not been fully understood. Using Conditional medium co-culture, quantitative high-throughput combinational screen (qHTCS), and genomic sequencing, we report that the RUNX1-PDGFBB-AKt pathway was significantly elevated in palbociclib-resistance cells. Inhibition of this axis can enhance the therapeutic efficacy of Palbociclib and surmount Palbociclib resistance both in vitro and in vivo. Mechanistically, we found that O-GlcNAc transferase (OGT) modifies RUNX1 with O-GlcNAcylation at Serine 252 (Ser252), thereby stabilizing RUNX1 protein expression, which is crucial in regulating PDGFBB expression. Significantly, clinical studies also confirm that RUNX1-PDGFBB-Akt pahtway was elevated in palbociclib-resistance patients. Collectively, these results reveal a previously unrecognized mechanism by which RUNX1-PDGFBB mediated palbociclib resistance, and provide valuable insights for the development of innovative therapeutic strategies in future clinical contexts.

2025-01-30 | GSE264264 | GEO

Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Response to CDK4/6 Inhibition in Metastatic HR+/HER2- Breast Cancer

Project description:Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i), combined with endocrine therapy, represent the standard treatment for metastatic HR+/HER2- breast cancer (mBC). Despite their established efficacy, intrinsic resistance affects approximately one-third of patients, posing a significant challenge and underscoring the importance of identifying reliable predictive biomarkers. This study utilizes single-cell RNA sequencing (scRNAseq) of metastatic site biopsies to unveil cellular and molecular biomarkers predictive of CDK4/6i response. Through this analysis, we have identified and validated the tumor-specific molecular biomarkers across two independent mBC patient cohorts using bulk RNAseq data from baseline fresh biopsies or FFPE slides of HR+/HER2- mBC patients prior to CDK4/6i treatment. Additionally, the data indicate that baseline predictors may include tumor-infiltrating cytotoxic NK and T lymphocytes, suggesting the potential utility of checkpoint inhibitors in CDK4/6i progressors. These potentially actionable insights underscore the importance of optimizing therapeutic strategies based on microenvironment-specific changes observed following disease progression.

2025-02-18 | GSE262288 | 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

RNA-seq from atirmociclib resistant versus sensitive and vehicle treated HR+ HER2- ZR751 breast cancer xenografts .

Project description:We investigated the mechanisms of acquired resistance to the CDK4 selective inhibitor atirmociclib in HR+ HER2- breast cancer in vivo, using the ZR751 xenograft model. Atirmociclib resistant tumors appeared after long-term (>50 day) treatment with atirmociclib. Tumor material was isolated from resistant (85-day treatment) as well as sensitive/vehicle treated (3-day) tumor bearing mice and subjected to RNA-seq analysis.

2025-03-31 | GSE288580 | GEO

FOXA1 phosphorylation by CDK4 prevents activation of novel chromatin regions and HER2 expression in breast cancer

Project description:Cyclin Dependent Kinase 4/6 inhibitors induce transcription in breast tumors via FOXA1 chromatin binding. The use of Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i) induce transcription in breast tumors. The control mechanism of such genomic changes and their physiological relevance are not elucidated yet. Now, we identified chromatin activation of tumors treated with CDK4/6i. These chromatin changes induce an increase of HER2 expression and signaling. Mechanically, our study demonstrates that FOXA1 is a new substrate of CDK4 and that its phosphorylation limits the binding of FOXA1 to conventional chromatin regions. Moreover, when patients are treated with CDK4/6i, a dephosphorylated FOXA1 binds to additional chromatin regions. By doing so, FOXA1 leads to an increase of HER2 expression and of the activation of HER2-MEK-ERK pathway in breast cancer patients. Accordingly, we might envision a clinical benefit of adding antiHER2 therapy to delay development of resistance and therefore, to prolong PFS in patients yet receiving CDK4/6i.

2023-09-01 | GSE231544 | GEO

AKT/mTOR/HER/PI3K family genes as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL (NCT01042379)

Project description:The AKT inhibitor MK2206 (M) was one of the experimental agents evaluated in I-SPY 2, a neoadjuvant platform trial for high risk, early stage breast cancer, and graduated in the HER2+, HR-, and HR-HER2+ signatures. Based on the hypotheses that since MK2206 is an enzymatic inhibitor of AKT, response to MK2206 may be predicted by the relative pre-treatment levels of AKT kinase substrates, in pre-defined analyses we assessed 10 genes in the HER-AKT-mTOR pathway to test their association with pCR (complete pathologic response) in the MK2206 arm, in both HER2+ and HER2- subsets. We also tested 9 genes genes previously associated with response to MK2206 in vitro and in the HER2+ metastatic setting, and performed exploratory association analyses using whole-transcriptome data to identify additional predictive signals outside the HER-AKT-mTOR pathway.

2020-09-20 | GSE149322 | GEO

Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Response to CDK4/6 Inhibition in Metastatic HR+/HER2- Breast Cancer

Project description:Single-Cell RNA Sequencing Identifies Molecular Biomarkers Predicting Response to CDK4/6 Inhibition in Metastatic HR+/HER2- Breast Cancer

| PRJNA1090971 | ENA

HR+/HER2- Breast Cancer Cell and Normal Breast Epithelial Cell Derived Exosome RNA Expression

Project description:AS a key medium for intercellular communication, exosome plays an important role in the occurrence and development of various forms of cancers, including breast cancer. However, the RNA from breast cancer-derived exosome remains to be explored. The HR+/HER2− breast cancer is the most common subgroup of breast cancer, we collected and primary cultured breast cancer and normal breast epithelial cells from three HR+/HER2− breast cancer patients, isolated the supernatant and extracted RNA from exosomes, and then performed microarray assays.

2023-10-01 | GSE207304 | GEO

AKT/mTOR/HER/PI3K family proteins and phospho-proteins as predictors of pCR for early stage breast cancer patients treated with the AKT inhibitor MK2206 in the I-SPY 2 TRIAL (NCT01042379)

Project description:The AKT inhibitor MK2206 (M) was one of the experimental agents evaluated in I-SPY 2, a neoadjuvant platform trial for high risk, early stage breast cancer, and graduated in the HER2+, HR-, and HR-HER2+ signatures. Based on the hypotheses that since MK2206 is an enzymatic inhibitor of AKT, response to MK2206 may be predicted by the relative pre-treatment levels of phosphorylation of AKT kinase substrates, in pre-defined analyses we assessed 26 well known proteins/phospho-proteins in the HER-AKT-mTOR pathway to test their association with pCR in the MK2206 arm, in both HER2+ and HER2- subsets. We specifically used laser capture microdissection (LCM)- enriched tumor epithelium cell isolates from the clinical biopsy specimens as the sample input for all protein pathway activation analysis, which has been shown to be critical in accurate measurement of ubiquitously expressed and activated signaling proteins. To the best of our knowledge, this work represents the first rigorous study of association between direct measurement of AKT pathway activation using phospho-protein activation levels and response to MK2206 performed in early stage breast cancer patients.

2020-09-20 | GSE150575 | GEO

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