GSE252944 Cholesterol biosynthesis inhibition synergizes with AKT inhibitors in triple-negative breast cancer

Contributors : Alissandra Hillis ; Alex Toker ; Ralitsa MadsenSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensTriple-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 negative selection CRISPR/Cas9 screen with PI3K  and AKT inhibitors to identify targetable synthetic lethalities in TNBC. We found that cholesterol homeostasis is 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 organoids of estrogen receptor (ER)-negative breast cancer. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBCs show dysregulated SREBP-2 activation in response to single agent or combination AKT inhibitor and pitavastatin, and this was rescued by inhibition of the cholesterol trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss promoted lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerabili...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research