Targeting Cholesterol Biosynthesis with Statins Synergizes with AKT Inhibitors in Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Triple-negative breast cancer (TNBC) presents significant challenges due to its heterogeneity, high recurrence, and limited targeted therapies.
• The phosphoinositide 3-kinase (PI3K)/AKT pathway is dysregulated in about 50% of TNBC cases, making it a key area for therapeutic intervention.
• Identifying synthetic lethalities is crucial for developing effective TNBC treatments.

Purpose of the Study:

• To identify targetable synthetic lethalities in TNBC by screening for vulnerabilities associated with PI3Kα and AKT inhibition.
• To investigate the role of cholesterol homeostasis as a collateral vulnerability in TNBC.
• To evaluate the therapeutic potential of combining AKT inhibitors with cholesterol-modulating agents in TNBC.

Main Methods:

• Genome-wide CRISPR/Cas9 screening was employed to identify synthetic lethal interactions with PI3Kα and AKT inhibitors.
• The study utilized in vitro cell line models, mouse TNBC xenografts, and patient-derived organoids (ER-negative and ER-positive) to assess drug efficacy.
• Mechanistic studies involved analyzing sterol regulatory element-binding protein 2 (SREBP-2) activation and cholesterol trafficking pathways, including the role of Niemann-Pick C1 (NPC1).

Main Results:

• Cholesterol homeostasis was identified as a collateral vulnerability specifically in TNBC when combined with AKT inhibition.
• The combination of pitavastatin (a cholesterol-lowering drug) and an AKT inhibitor demonstrated synergistic cytotoxicity against TNBC cells and xenografts.
• This combination therapy was ineffective in estrogen receptor-positive (ER-positive) breast cancer models, indicating TNBC specificity.
• Mechanistically, the combination impaired SREBP-2 activation in TNBC cells, a process linked to cholesterol trafficking via NPC1.

Conclusions:

• The study identifies a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin, mediated by disrupted cholesterol trafficking.
• This combination therapy, utilizing two FDA-approved drugs, effectively induces cell death in TNBC models.
• The findings strongly support the clinical evaluation of combining AKT inhibitors with pitavastatin for TNBC treatment.