ArticleThe Journal of clinical investigation2022
SIK2 inhibition enhances PARP inhibitor activity synergistically in ovarian and triple-negative breast cancers.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 1 of them a synthesis that pooled it.
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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
26 citing papers in PubMed, 1 synthesis or guideline pooled it, 39 citations in OpenAlex.
- Exploring the efficacy of PARP inhibitors in metastatic castration-resistant prostate cancer with homologous recombination repair alteration: a meta-analysis based on subgroups and reconstructed individual patient data.International journal of surgery (London, England) · 2026Pooled it
- SIK inhibitor HG-9-91-01 suppresses the pathogenic activity of fibroblast-like synoviocytes in rheumatoid arthritis.RMD open · 2026Article
- Transcriptomic analysis of tissue-resident memory T cells of the fallopian tube reveals a precursor immune surveillance network for ovarian cancer prevention.Nature communications · 2026Article
- Inhibition of SIK2 and SIK3 induces adaptive ER-phagy and creates a therapeutic vulnerability in ovarian cancer.Research square · 2026Article
- The impactful role of the HDACs in the regulation of gene expression and as targets for disease therapy.Science advances · 2026Review
- Targeting SIK2 with GRN-300 Potentiates Paclitaxel Efficacy in Triple-Negative Breast Cancer.Cancers · 2026Article
- Inhibition of salt-inducible kinases reprograms T cells and antitumor immunity in ovarian cancer.Nature immunology · 2026Article
- A Review of SIK2 in Ovarian Cancer: Function and Emerging Targeted Therapies.OncoTargets and therapy · 2026Review
- Therapeutic targeting of post-translational modifications in ovarian cancer: mechanisms and clinical applications.Journal of ovarian research · 2025Review
- A FANCD2 gene mutation case analysis providing potential insights into the molecular mechanisms of gastric adenocarcinoma: A case report.Oncology letters · 2025Article
- Jab1 regulates HRR mRNA stability to modulate PARP inhibitor sensitivity in triple-negative breast cancer.Molecular cancer · 2025Article
- Class IIa HDACs Are Important Signal Transducers with Unclear Enzymatic Activities.Biomolecules · 2025Review
- Salt-inducible kinase 2 confers radioresistance in colorectal cancer by facilitating homologous recombination repair.MedComm · 2025Article
- SIK2 activates the autophagy‒apoptosis pathway through SP1 regulation to inhibit the progression of hepatocellular carcinoma.Frontiers in pharmacology · 2025Article
- SIK2 inhibitor SIC-19 enhances the sensitivity of PARP inhibitors in triple-negative breast cancers and pancreatic cancers.Oncology research · 2025Article
- Abrogation of KLF5 sensitizesActa biochimica et biophysica Sinica · 2024Article
- Discovery of Clinical Candidate GLPG3970: A Potent and Selective Dual SIK2/SIK3 Inhibitor for the Treatment of Autoimmune and Inflammatory Diseases.Journal of medicinal chemistry · 2024Article
- Optimization of Selectivity and Pharmacokinetic Properties of Salt-Inducible Kinase Inhibitors that Led to the Discovery of Pan-SIK Inhibitor GLPG3312.Journal of medicinal chemistry · 2024Article
- Molecular mechanism of PARP inhibitor resistance.Oncoscience · 2024Review
- HDAC-driven mechanisms in anticancer resistance: epigenetics and beyond.Cancer drug resistance (Alhambra, Calif.) · 2024Review
Corrections and comments
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Authors and funding
22 authors at 3 institutions in 2 countries.
Funding
Abstract
Poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) have had an increasing role in the treatment of ovarian and breast cancers. PARP inhibitors are selectively active in cells with homologous recombination DNA repair deficiency caused by mutations in BRCA1/2 and other DNA repair pathway genes. Cancers with homologous recombination DNA repair proficiency respond poorly to PARP inhibitors. Cancers that initially respond to PARP inhibitors eventually develop drug resistance. We have identified salt-inducible kinase 2 (SIK2) inhibitors, ARN3236 and ARN3261, which decreased DNA double-strand break (DSB) repair functions and produced synthetic lethality with multiple PARP inhibitors in both homologous recombination DNA repair deficiency and proficiency cancer cells. SIK2 is required for centrosome splitting and PI3K activation and regulates cancer cell proliferation, metastasis, and sensitivity to chemotherapy. Here, we showed that SIK2 inhibitors sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. SIK2 inhibitors decreased PARP enzyme activity and phosphorylation of class-IIa histone deacetylases (HDAC4/5/7). Furthermore, SIK2 inhibitors abolished class-IIa HDAC4/5/7-associated transcriptional activity of myocyte enhancer factor-2D (MEF2D), decreasing MEF2D binding to regulatory regions with high chromatin accessibility in FANCD2, EXO1, and XRCC4 genes, resulting in repression of their functions in the DNA DSB repair pathway. The combination of PARP inhibitors and SIK2 inhibitors provides a therapeutic strategy to enhance PARP inhibitor sensitivity for ovarian cancer and TNBC.
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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.