ArticleCell reports2023
Sequential activation of E2F via Rb degradation and c-Myc drives resistance to CDK4/6 inhibitors in breast cancer.
Article in Cell reports, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed.
- Ru3: a novel ruthenium-based compound overcomes cisplatin resistance in non-small cell lung cancer via the E2F2-IGFBP3-GPX4 pathway.Apoptosis : an international journal on programmed cell death · 2026Article
- CDK8/19 inhibition prevents adaptive resistance to CDK4/6 inhibitors in vitro and in vivo.Cell reports. Medicine · 2026Article
- Molecular signatures of triple-negative breast cancer cells acquiring palbociclib resistance via continuous exposure.Oncology letters · 2026Article
- Molecular modulators of cyclin-dependent kinase 4/6 inhibitor response in experimental glioma identified through genome-wide CRISPR-Cas9 screening.Neuro-oncology · 2026Article
- Deciphering Site-Specific Regulatory Networks of the Kinesin Protein KIF21A Through Integrative Phosphoproteomic Analysis.International journal of molecular sciences · 2026Article
- HAUS1-mediated activation of CDK4 transcription enhances proliferation, invasion and migration in hepatocellular carcinoma.Cancer gene therapy · 2026Article
- TP53 mutation is associated with shorter treatment duration with CDK4/6 inhibitors, but not with immune checkpoint inhibitors, in ER-positive/HER2-negative breast cancer: real-world perspective.Breast cancer research : BCR · 2026Article
- Celecoxib potentiates ribociclib-induced apoptosis and anti-tumor activity by co-targeting COX-2/NF-κB and PI3K/AKT/mTOR pathways in hormone receptor-positive/HER2-negative breast cancer.Apoptosis : an international journal on programmed cell death · 2026Article
- Chromatin association promotes UBR5-mediated degradation of Rb.bioRxiv : the preprint server for biology · 2026Article
- Homologous recombination deficiency and hemizygosity drive resistance in breast cancer.Nature · 2026Article
- m5C RNA methylation is dysregulated by oncogenic herpesviruses via c-Myc signaling to counteract host antiviral factors.Nucleic acids research · 2026Article
- A machine learning assay to predict disease recurrence in hormone receptor-positive breast cancer.ESMO open · 2026Article
- Mathematical analysis of G1/S sub-networks in hematopoietic proliferation: Sequential and lineage-specific activation.iScience · 2026Article
- Article
- Slowing the growth of drug-resistant tumors.eLife · 2025Article
- Next-generation sequencing methodologies to identify patients for targeted therapy: focus on HR+/HER2- metastatic breast cancer.Pathologica · 2025Review
- Identification of an E2Fs-based gene signature for predicting prognosis and therapeutic response in colorectal cancer.Discover oncology · 2025Article
- Dual targeting of CDK4/6 and CDK7 augments tumor response and antitumor immunity in breast cancer models.The Journal of clinical investigation · 2025Article
- Using single-cell perturbation screens to decode the regulatory architecture of splicing factor programs.Nucleic acids research · 2025Article
- Review
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12 authors.
Funding
Abstract
Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are key therapeutic agents in the management of metastatic hormone-receptor-positive breast cancer. However, the emergence of drug resistance limits their long-term efficacy. Here, we show that breast cancer cells develop CDK4/6i resistance via a sequential two-step process of E2F activation. This process entails retinoblastoma (Rb)-protein degradation, followed by c-Myc-mediated amplification of E2F transcriptional activity. CDK4/6i treatment halts cell proliferation in an Rb-dependent manner but dramatically reduces Rb-protein levels. However, this reduction in Rb levels insufficiently induces E2F activity. To develop CDK4/6i resistance, upregulation or activating mutations in mitogenic or hormone signaling are required to stabilize c-Myc levels, thereby augmenting E2F activity. Our analysis of pre-treatment tumor samples reveals a strong correlation between c-Myc levels, rather than Rb levels, and poor therapeutic outcomes after CDK4/6i treatment. Moreover, we propose that proteasome inhibitors can potentially reverse CDK4/6i resistance by restoring Rb levels.
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