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

Hillis, A;Martin, T;Manchester, H;Hogstrom, J;Zhang, N;Lecky, E;Kozlova, N;Persky, N;Root, D;Brown, M;Cichowski, K;Elledge, S;Muranen, T;Fruman, D;Barry, S;Clohessy, J;Madsen, R;Toker, A;

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 PI3K? 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 cytotoxicityin 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.