Cholesterol biosynthesis inhibition synergizes with AKT inhibitors in triple-negative breast cancer

Alissandra L. Hillis (Lead / Corresponding author), Timothy D. Martin, Haley E. Manchester, Jenny M. Hogstrom, Na Zhang, Emmalyn Lecky, Nina Kozlova, Nicole S. Persky, David E. Root, Myles Brown, Karen Cichowski, Stephen J. Elledge, Taru Muranen, David A. Fruman, Simon T. Barry, John G. Clohessy, Ralitsa R. Madsen, Alex Toker (Lead / Corresponding author)

Research output: Working paper/PreprintPreprint


Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer deaths due to its molecular heterogeneity, high recurrence rate and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. We performed a genome-wide CRISPR/Cas9 screen with PI3Kα and AKT inhibitors to find targetable synthetic lethalities in TNBC. We identified cholesterol homeostasis 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. This 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. Our work motivates combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC.
Original languageEnglish
Number of pages47
Publication statusPublished - 16 Jan 2024


  • Cancer biology


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