ArticleClinical cancer research : an official journal of the American Association for Cancer Research2024
Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor-positive Breast Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 34 citations in OpenAlex.
- Biomarkers of response to neoadjuvant palbociclib plus anastrozole in endocrine-resistant estrogen receptor-positive/HER2-negative breast cancer: a phase 2 trial.Nature communications · 2026Trial
- Discovery of azaindole/indole-fused pyrimidine tetracyclic scaffolds as novel potent CDK7 inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2026Article
- Sensitizing tumor response to topoisomerase I antibody-drug conjugate by selective CDK7 inhibition.Science advances · 2026Article
- CDK8/19 inhibition prevents adaptive resistance to CDK4/6 inhibitors in vitro and in vivo.Cell reports. Medicine · 2026Article
- MNAT1 in gastrointestinal cancers: mechanistic insights and therapeutic strategies-a narrative review.Journal of gastrointestinal oncology · 2026Review
- Targeting CDKs in the RNAPII transcription cycle.Nature reviews. Drug discovery · 2026Review
- Nucleic sexual hormone receptor signaling pathways in breast cancer: function regulation, crosstalk, and therapeutic implications.NPJ precision oncology · 2026Review
- Discovery of a selective CDK7 PROTAC against acute leukemia with low platelet toxicity.Leukemia · 2026Article
- Establishment of a prognostic model for hepatocellular carcinoma patients based on bioinformatics analysis and exploration of prognostic biomarker EPPK1.Scientific reports · 2026Article
- Metabolic orchestration driven by GGCT: diverting glutamine to glutathione biosynthesis while enhancing glucose anaplerosis for tumor proliferation.Cell death & disease · 2026Article
- Lack of synergy between AR-targeted therapies and PARP inhibitors in homologous recombination-proficient prostate cancer.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Dalpiciclib induced hepatitis B virus reactivation leading to liver failure: a rare case report and review of the literature.Frontiers in medicine · 2026Article
- Article
- The Anticancer Effect of Kaempferol Through Downregulation of CDKs and PD-L1 in Triple-Negative Breast Cancer Cells.Cancers · 2025Article
- CDK7-targeted therapy effectively disrupts cell cycle progression and oncogenic signaling in head and neck cancer.Signal transduction and targeted therapy · 2025Article
- The novel role of DUSP4 in suppressing ferroptosis and promoting cytotoxicity of CD8British journal of cancer · 2025Article
- Cold atmospheric plasma restores fulvestrant sensitivity by inhibiting CCND3 in the drug-resistant breast cancer cells.Scientific reports · 2025Article
- Dual targeting of CDK4/6 and CDK7 augments tumor response and antitumor immunity in breast cancer models.The Journal of clinical investigation · 2025Article
- Combined inhibition of KAT6A/B and Menin reverses estrogen receptor-driven gene expression programs in breast cancer.Cell reports. Medicine · 2025Article
- CRISPR screening approaches in breast cancer research.Cancer metastasis reviews · 2025Review
Corrections and comments
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Authors and funding
31 authors at 6 institutions in 3 countries.
Funding
Abstract
purposeResistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms. EXPERIMENTAL
designWe conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide CRISPR/Cas9 knockout screens to identify potential therapeutic vulnerabilities in CDK4/6i-resistant models.
resultsWe found that the on-target antitumor effects of CDK7 inhibition in ER+ breast cancer are in part p53 dependent, and involve cell cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ET and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118; however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Finally, genome-wide CRISPR/Cas9 knockout screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i-resistant models.
conclusionsTaken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ breast cancer. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors of sensitivity to CDK7i-based treatments.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.