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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288580 | GEO | 2025/03/31

REPOSITORIES: GEO

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

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

| PRJNA1218627 | ENA

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

Targeting ferroptosis resistance re-sensitizes metastatic HR+ HER2- breast cancer to palbociclib-hormone therapy

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

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

Transcription profiling of human MCF7 wt and MCF7/HER2-18 xenografts

Project description:To investigate molecular mechanisms of resistance, we used two different in vivo xenograft models of estrogen receptor-positive (ER+) breast cancer, with or without HER2 over-expression (MCF7/HER2-18 and MCF7 wt, respectively). Mice with established tumors were assigned to the following treatment groups: continued estrogen supplementation (E2), estrogen deprivation (ED), ED plus tamoxifen (Tam), all with or without the EGFR tyrosine kinase inhibitor gefinitinib (G). Another group received ED plus the antiestrogen fulvestrant (MCF7 wt only). Tumors with acquired or de novo resistance to these endocrine therapies were profiled for mRNA expression using Affymetrix Genechip arrays. This SuperSeries is composed of the following subset Series:; GSE8139: Expression data from MCF7/HER2-18 xenografts; GSE8140: Expression data from MCF7 wt xenografts Experiment Overall Design: MCF7 xenografts were established in ovariectomized five to six week-old nu/nu athymic nude mice supplemented with 0.25 mg 21 day release estrogen pellets by inoculating subcutaneously (s.c.) 5E-6 cells. When tumors reached the size of 150-200 mm3 (3-5 weeks), the animals were randomly allocated to continued estrogen (E2), continued estrogen with gefitinib (E2+G; 100mg/kg, 5 days/week), estrogen withdrawal alone (ED; by removal of the estrogen pellets), and estrogen withdrawal plus tamoxifen citrate (Tam; 500 microg/animal s.c. in peanut oil, 5 days/week), with either gefitinib (Tam+G; 100mg/kg, 5 days/week) or vehicle (1% Tween 80) administered via gavage, as well as estrogen withdrawal plus fulvestrant (ICI 182,780) in the MCF7 wt model (Fulv; 5mg/mouse s.c. once weekly), and estrogen withdrawal with gefitinib (ED+G). Tumors were harvested for molecular studies when they became resistant to treatment and reached the size of 1000 mm3 (n=7). Experiment Overall Design: Refer to individual Series

2008-12-05 | E-GEOD-8141 | biostudies-arrayexpress

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

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

| PRJNA1101560 | ENA

Dual HER2 targeting impedes growth of HER2 gene-amplified uterine serous carcinoma xenografts.

Project description:PurposeUterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that commonly harbors HER2 gene amplification. We investigated the effectiveness of HER2 inhibition using lapatinib and trastuzumab in vitro and in xenografts derived from USC cell lines and USC patient-derived xenografts.Experimental designImmunohistochemistry and FISH were performed to assess HER2 expression in 42 primary USC specimens. ARK1, ARK2, and SPEC2 cell lines were treated with trastuzumab or lapatinib. Cohorts of mice harboring xenografts derived from ARK2 and SPEC2 cell lines and EnCa1 and EnCa2 primary human USC samples were treated with either vehicle, trastuzumab, lapatinib, or the combination of trastuzumab and lapatinib. Acute and chronic posttreatment tumor samples were assessed for downstream signaling alterations and examined for apoptosis and proliferation.ResultsHER2 gene amplification (24%) correlated significantly with HER2 protein overexpression (55%). All models were impervious to single-agent trastuzumab treatment. Lapatinib decreased in vitro proliferation of all cell lines and in vivo growth of HER2-amplified xenografts (ARK2, EnCa1). In addition, dual therapy with trastuzumab and lapatinib resulted in significant antitumor activity only in ARK2 and EnCa1 tumors. Dual HER2 therapy induced on target alteration of downstream MAPK and PI3K pathway mediators only in HER2-amplified models, and was associated with increased apoptosis and decreased proliferation.ConclusionsAlthough trastuzumab alone did not impact USC growth, dual anti-HER2 therapy with lapatinib led to improved inhibition of tumor growth in HER2-amplified USC and may be a promising avenue for future investigation.

| S-EPMC4268047 | biostudies-literature

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