ArticleProceedings of the National Academy of Sciences of the United States of America2023
Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 15 citations in OpenAlex.
- Decoding drug-responsive cell subpopulations in triple-negative breast cancer using single-cell multiomics.iScience · 2026Article
- CDK12 Inactivation Attenuates Prostate Cancer Progression by Inhibiting BNIP3-Mediated Mitophagy.Cell proliferation · 2026Article
- Context-aware gene dependency modeling via graph attention networks for precision oncology.Journal of translational medicine · 2025Article
- Targeting Transcriptional Cyclin-Dependent Kinases in Cancer.Molecular cancer therapeutics · 2025Review
- CRISPR screening approaches in breast cancer research.Cancer metastasis reviews · 2025Review
- New insights into the dule roles CDK12 in human cancers: Mechanisms and interventions for cancer therapy.Journal of pharmaceutical analysis · 2025Review
- Absence of CDK12 in oocyte leads to female infertility.Cell death & disease · 2025Article
- Physiological and pathological roles of the transcriptional kinases CDK12 and CDK13 in the central nervous system.Cell death and differentiation · 2025Review
- Cyclin-dependent protein kinases and cell cycle regulation in biology and disease.Signal transduction and targeted therapy · 2025Review
- Mediator kinase inhibition impedes transcriptional plasticity and prevents resistance to ERK/MAPK-targeted therapy in KRAS-mutant cancers.NPJ precision oncology · 2024Article
- Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
Corrections and comments
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
Evidence has long suggested that epidermal growth factor receptor (EGFR) may play a prominent role in triple-negative breast cancer (TNBC) pathogenesis, but clinical trials of EGFR inhibitors have yielded disappointing results. Using a candidate drug screen, we identified that inhibition of cyclin-dependent kinases 12 and 13 (CDK12/13) dramatically sensitizes diverse models of TNBC to EGFR blockade. This combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and translation-linked turnover of driver oncoproteins, including MYC. A genome-wide CRISPR/Cas9 screen identified the CCR4-NOT complex as a major determinant of sensitivity to the combination therapy whose loss renders 4E-BP1 unresponsive to drug-induced dephosphorylation, thereby rescuing MYC translational suppression and promoting MYC stability. The central roles of CCR4-NOT and 4E-BP1 in response to the combination therapy were further underscored by the observation of CNOT1 loss and rescue of 4E-BP1 phosphorylation in TNBC cells that naturally evolved therapy resistance. Thus, pharmacological inhibition of CDK12/13 reveals a long-proposed EGFR dependence in TNBC that functions through the cooperative regulation of translation-coupled oncoprotein stability.
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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.