Triple-negative breast cancer (TNBC) is by far the deadliest subtype of breast malignancies. Although few effective therapies exist for TNBC treatment, dysregulation of the PI3 kinase/AKT intracellular signaling pathway is frequently seen in patients diagnosed with the cancer. Researchers led by Ludwig Harvard’s Alex Toker and alumnus Alissandra Hillis conducted a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to expose synthetic lethalities that might be exploited for TNBC therapy. They reported in an October paper in Cancer Research that treatment with AKT inhibitors makes TNBC cells exceptionally vulnerable to disruptions in their cholesterol balance (homeostasis) induced by a statin drug (pitavastatin). Single agent or combination treatment with the two drugs impaired activation of the transcription factor SREBP-2, which is critical to cholesterol biosynthesis and homeostasis. The researchers found that combining an FDA-approved AKT inhibitor with pitavastatin kills TNBC cells in patient-derived estrogen receptor (ER)–negative breast cancer organoids and impairs tumor growth and decreases tumor size in mice bearing xenografts of TNBC tumors. ER-positive cell lines and organoids showed no such susceptibility to the drug combination. Alex, Alissandra and colleagues suggest the findings support a clinical trial to evaluate the benefits of the drug combination for TNBC therapy, especially since both drugs involved are already in clinical use today.
Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer
Cancer Research, 2024 October 1