ArticleOncogene2020
Tumour kinome re-wiring governs resistance to palbociclib in oestrogen receptor positive breast cancers, highlighting new therapeutic modalities.
Article in Oncogene, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
56 citing papers in PubMed, 88 citations in OpenAlex.
- Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor- and ErbB2-positive Breast Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2022Trial
- Biomarkers of Response and Resistance to Palbociclib Plus Letrozole in Patients With ERClinical cancer research : an official journal of the American Association for Cancer Research · 2022Trial
- Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial.Cell research · 2021Trial
- Estradiol-associated extracellular signaling in the human breastOncoimmunology · 2026Article
- Porosity-engineered long-acting protopanaxadiol microspheres prevent CDK4/6 inhibitor-induced myelosuppression.Materials today. Bio · 2026Article
- Proteomic approaches for interrogating kinase signaling networks.The Journal of investigative dermatology · 2026Article
- Emerging Strategies to Inhibit the G1/S Transition for Cancer Therapy.Cancer research · 2026Review
- Deciphering molecular pathways in urological cancers: A gateway to precision therapeutics.Journal of advanced research · 2026Review
- Cytotoxic and proapoptotic effects of alizarin in mice with Ehrlich solid tumor: novel insights into ERα-mediated MDM2/p-Rb/E2F1 signaling pathway.Naunyn-Schmiedeberg's archives of pharmacology · 2025Article
- WEE1 inhibition delays resistance to CDK4/6 inhibitor and antiestrogen treatment in ER+ MCF7 cells.NPJ systems biology and applications · 2025Article
- Emerging Mechanisms of Therapy Resistance in Metastatic ER+ Breast Cancer.Endocrinology · 2025Review
- Functional Analysis of the PI3K/AKT/mTOR Pathway Inhibitor, Gedatolisib, Plus Fulvestrant with and Without Palbociclib in Breast Cancer Models.International journal of molecular sciences · 2025Article
- Review
- Targeting WEE1 Kinase for Breast Cancer Therapeutics: An Update.International journal of molecular sciences · 2025Review
- Proteogenomic discovery ofScience advances · 2025Article
- Article
- Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i): Mechanisms of resistance and where to find them.Breast (Edinburgh, Scotland) · 2025Review
- TFAP2C-DDR1 axis regulates resistance to CDK4/6 inhibitor in breast cancer.Cancer letters · 2025Article
- Emerging opportunities to treat drug-resistant breast cancer: Discovery of novel small-molecule inhibitors against different targets.Frontiers in pharmacology · 2025Review
- CDK4/6 Inhibitor Resistance in ER+ Breast Cancer.Advances in experimental medicine and biology · 2025Review
Corrections and comments
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Authors and funding
19 authors at 4 institutions in 3 countries.
Funding
Abstract
Combination of CDK4/6 inhibitors and endocrine therapy improves clinical outcome in advanced oestrogen receptor (ER)-positive breast cancer, however relapse is inevitable. Here, we show in model systems that other than loss of RB1 few gene-copy number (CN) alterations are associated with irreversible-resistance to endocrine therapy and subsequent secondary resistance to palbociclib. Resistance to palbociclib occurred as a result of tumour cell re-wiring leading to increased expression of EGFR, MAPK, CDK4, CDK2, CDK7, CCNE1 and CCNE2. Resistance altered the ER genome wide-binding pattern, leading to decreased expression of 'classical' oestrogen-regulated genes and was accompanied by reduced sensitivity to fulvestrant and tamoxifen. Persistent CDK4 blockade decreased phosphorylation of tuberous sclerosis complex 2 (TSC2) enhancing EGFR signalling, leading to the re-wiring of ER. Kinome-knockdown confirmed dependency on ERBB-signalling and G2/M-checkpoint proteins such as WEE1, together with the cell cycle master regulator, CDK7. Noteworthy, sensitivity to CDK7 inhibition was associated with loss of ER and RB1 CN. Overall, we show that resistance to CDK4/6 inhibitors is dependent on kinase re-wiring and the redeployment of signalling cascades previously associated with endocrine resistance and highlights new therapeutic networks that can be exploited upon relapse after CDK4/6 inhibition.
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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.