ArticleCell death & disease2020
Pan-cancer analysis reveals synergistic effects of CDK4/6i and PARPi combination treatment in RB-proficient and RB-deficient breast cancer cells.
Article in Cell death & disease, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed.
- Antitumor activity and structure-activity relationship of poly (ADP-ribose) polymerase (PARP)-based dual inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Induced pluripotent stem cell-derived models of malignant nerve sheath tumor progression mimic glial to neuro-mesenchymal transition and uncover therapeutic opportunities.Nature communications · 2026Article
- Real-World Outcomes of CDK4/6 Inhibitors in Germline BRCA1/2-Mutated Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: Turkish Oncology Group (TOG) Study.Current oncology (Toronto, Ont.) · 2026Article
- Sequencing PARP inhibitors in breast cancer: lessons learned and emerging insights.NPJ breast cancer · 2026Review
- TRMT6/61A-mediated tRNA m1A methylation promotes codon-dependent TAB2 translation and drives AML progression.Molecular medicine (Cambridge, Mass.) · 2026Article
- A macro-micro-macro radiogenomic framework identifies FIBCD1 as a key immune-modulating biomarker in breast cancer.Journal of translational medicine · 2025Article
- Temporal control of human DNA replication licensing by CDK4/6-RB signalling and chemical genetics.Nature communications · 2025Article
- Fused pyrido[3,4-D]pyrimidine moiety with phthalazinone ring accelerate dual inhibition of PARP1 and CDK4 in triple-negative breast cancer: a hybrid design with computational investigation through molecular modeling and quantum mechanics.Journal of molecular modeling · 2025Article
- Biomimetic Targeted Co-Delivery System Engineered from Genomic Insights for Precision Treatment of Osteosarcoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Astragalus polysaccharides sensitize ovarian cancer stem cells to PARPi by inhibiting mitophagy via PINK1/Parkin signaling.iScience · 2024Article
- Effects of combined use of ribociclib with PARP1 inhibitor on cell kinetics in breast cancer.Oncology letters · 2024Article
- CDK4/6 inhibitor abemaciclib combined with low-dose radiotherapy enhances the anti-tumor immune response to PD-1 blockade by inflaming the tumor microenvironment in Rb-deficient small cell lung cancer.Translational lung cancer research · 2024Article
- Seize the engine: Emerging cell cycle targets in breast cancer.Clinical and translational medicine · 2024Review
- m5C methylation modification guides the prognostic value and immune landscapes in acute myeloid leukemia.Aging · 2023Article
- Oleic Acid Dissolves cGAS-DNA Phase Separation to Inhibit Immune Surveillance.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Leveraging the replication stress response to optimize cancer therapy.Nature reviews. Cancer · 2023Review
- Molecular intrinsic subtypes, genomic, and immune landscapes of BRCA-proficient but HRD-high ER-positive/HER2-negative early breast cancers.Breast cancer research : BCR · 2022Article
- CDK4/6 inhibitors downregulate the ubiquitin-conjugating enzymes UBE2C/S/T involved in the ubiquitin-proteasome pathway in ER + breast cancer.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2022Article
- Inhibition of PKM2 Enhances Sensitivity of Olaparib to Ovarian Cancer Cells and Induces DNA Damage.International journal of biological sciences · 2022Article
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
DNA damage results in mutations and plays critical roles in cancer development, progression, and treatment. Targeting DNA damage response in cancers by inhibiting poly-(ADP-ribose) polymerases (PARPs) offers an important therapeutic strategy. However, the failure of PARP inhibitors to markedly benefit patients suggests the necessity for developing new strategies to improve their efficacy. Here, we show that the expression of cyclin-dependent kinase 4/6 (CDK4/6) complex members significantly correlates with mutations (as proxies of DNA damages), and that the combination of CDK4/6 and PARP inhibitors shows synergy in both RB-proficient and RB-deficient breast cancer cells. As PARPs constitute sensors of DNA damage and are broadly involved in multiple DNA repair pathways, we hypothesized that the combined inhibition of PARPs and DNA repair (or repair-related) pathways critical for cancer (DRPCC) should show synergy. To identify druggable candidate DRPCC(s), we analyzed the correlation between the genome-wide expression of individual genes and the mutations for 27 different cancer types, assessing 7146 exomes and over 1,500,000 somatic mutations. Pathway enrichment analyses of the top-ranked genes correlated with mutations indicated "cell cycle pathway" as the top candidate DRPCC. Additionally, among functional cell-cycle complexes, the CDK4/6 complex showed the most significant negative correlation with mutations, also suggesting that combined CDK4/6 and PARP inhibition might exhibit synergy. Furthermore, combination treatment showed synergy in not only RB-proficient but also RB-deficient breast cancer cells in a reactive oxygen species-dependent manner. These findings suggest a potential therapeutic strategy to improve the efficacy of PARP and CDK4/6 inhibitors in cancer treatment.
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