Olaparib synergy screen reveals Exemestane induces replication stress in triple-negative breast cancer

Area of Science:

• Oncology
• Pharmacology
• Molecular Biology

Background:

• Triple-negative breast cancer (TNBC) has a poor prognosis and limited targeted therapies.
• PARP inhibitors (PARPi) are effective in BRCA1/2-mutant TNBC but not in most BRCA-proficient cases.
• Combination therapies are needed to expand PARPi efficacy to a broader TNBC population.

Purpose of the Study:

• To identify novel synergistic drug combinations with Olaparib for TNBC treatment.
• To investigate the mechanistic basis of synergy between Olaparib and Exemestane.
• To evaluate the efficacy and safety of the Olaparib-Exemestane combination in preclinical models.

Main Methods:

• Screening of 166 FDA-approved oncology drugs for synergy with Olaparib in TNBC cell lines.
• Assessment of IC50 values, clonogenicity, DNA damage, and apoptosis.
• Mechanistic studies involving reactive oxygen species (ROS) and oxidative stress.
• Evaluation of tumor growth inhibition in a murine xenograft model.
• Gene Ontology (GO) and KEGG pathway enrichment analysis.

Main Results:

• Exemestane demonstrated synergy with Olaparib, significantly reducing IC50 values and improving clonogenicity.
• The combination increased DNA damage and apoptosis in TNBC cells.
• Exemestane induced replication stress via ROS generation and oxidative stress, explaining the synergy.
• The Olaparib-Exemestane combination showed enhanced tumor growth inhibition in vivo compared to single agents.
• The combination exhibited low cytotoxicity towards normal breast epithelial cells.

Conclusions:

• Exemestane is a novel synergistic partner for Olaparib in TNBC treatment, particularly for BRCA-proficient tumors.
• The combination's efficacy is mediated by induced replication stress and oxidative stress.
• The Olaparib-Exemestane combination represents a promising therapeutic strategy for TNBC with a favorable safety profile.