1. Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer.
- Author
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Hillis, Alissandra, Martin, Timothy, Manchester, Haley, Högström, Jenny, Zhang, Na, Lecky, Emmalyn, Kozlova, Nina, Lee, Jonah, Persky, Nicole, Root, David, Brown, Myles, Cichowski, Karen, Elledge, Stephen, Muranen, Taru, Fruman, David, Barry, Simon, Clohessy, John, Madsen, Ralitsa, and Toker, Alex
- Subjects
Triple Negative Breast Neoplasms ,Humans ,Animals ,Mice ,Cholesterol ,Female ,Proto-Oncogene Proteins c-akt ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Quinolines ,Xenograft Model Antitumor Assays ,Drug Synergism ,Cell Line ,Tumor ,Sterol Regulatory Element Binding Protein 2 ,Cell Proliferation - 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.
- Published
- 2024