ArticleCancer research2024
Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer.
Article in Cancer research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 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
28 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Pooled it
- Article
- Sterol regulatory element‑binding proteins: Master regulators of lipid metabolic reprogramming in cancer and emerging therapeutic targets (Review).Oncology reports · 2026Review
- Emerging roles of the metabolic regulator 3-hydroxy-3-methylglutaryl coenzyme-CoA reductase in human cancers: From biology to therapeutics.Genes & diseases · 2026Review
- Integrative Raman Spectroscopy and Multi-Omics Analysis of Lipid and Matrix Protein Heterogeneity in Triple-Negative Breast Cancer.Chemical & biomedical imaging · 2026Article
- Nobiletin and polydatin synergistically alleviate triple-negative breast cancer liver metastasis via suppressing ECM1a-mediated fatty acid biosynthesis.Acta pharmacologica Sinica · 2026Article
- NUDT21-mediated Alternative Polyadenylation of CDK19 Reprograms Cholesterol Biosynthesis to Drive Colorectal Cancer Progression.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Dynamic Metabolic States in TNBC: Orchestrating Spatiotemporal Adaptation and Therapy.Oncology research · 2026Review
- Exploring Lipid Metabolic Reprogramming: Mechanistic Insights and Implications for Tumor Radiotherapy.International journal of biological sciences · 2026Review
- Long Non-Coding RNA PVT1 Promotes Doxorubicin Resistance by Inhibiting Ferroptosis in Breast Cancer.Breast cancer (Dove Medical Press) · 2026Article
- Lipid Metabolic Reprogramming in Breast Cancer: Mechanisms and Emerging Therapeutic Strategies.Breast cancer (Dove Medical Press) · 2026Review
- Overcoming immunotherapy resistance in triple-negative breast cancer: a critical review of mast cell plasticity, metabolic reprogramming, and organoid models.Frontiers in immunology · 2026Review
- The Impact of IGFBP6 Knockdown on Cholesterol Metabolism in Breast Cancer Cells.Current medicinal chemistry · 2026Article
- Investigating the role of MYLK2 in breast cancer prognosis and assessing its clinical application value.Scientific reports · 2025Article
- Targeting Host Dependency Factors: A Paradigm Shift in Antiviral Strategy Against RNA Viruses.International journal of molecular sciences · 2025Review
- Gene Expression Profiles Modulated by Lipophilic Sea Buckthorn (Food science & nutrition · 2025Article
- Cholesterol metabolism and cancer: Molecular mechanisms, immune regulation and an epidemiological perspective (Review).International journal of molecular medicine · 2025Review
- Pitavastatin counteracts venetoclax resistance mechanisms in acute myeloid leukemia by depleting geranylgeranyl pyrophosphate.bioRxiv : the preprint server for biology · 2025Article
- Statins in the context of precision cancer medicine: important factors to consider.Medical oncology (Northwood, London, England) · 2025Review
- Mevalonate Biosynthesis is a Metabolic Vulnerability of Gemcitabine-resistant Pancreatic Cancer.bioRxiv : the preprint server for biology · 2025Article
Corrections and comments
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Authors and funding
19 authors.
Funding
Abstract
Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer patient deaths due to extensive molecular heterogeneity, high recurrence rates, and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. Here, we performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. Cholesterol homeostasis was identified as a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro in mouse TNBC xenografts and in patient-derived estrogen receptor (ER)-negative breast cancer organoids. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBC cells showed impaired sterol regulatory element-binding protein 2 (SREBP-2) activation in response to single-agent or combination treatment with AKT inhibitor and pitavastatin, which was rescued by inhibition of the cholesterol-trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss caused lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels, and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. These findings support combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC. Significance: Two FDA-approved compounds, AKT inhibitors and pitavastatin, synergize to induce cell death in triple-negative breast cancer, motivating evaluation of the efficacy of this combination in clinical trials.
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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.