Modeling Therapy Resistance in BRCA1/2-Mutant Cancers

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• PARP inhibitors are effective against BRCA1/2-mutant tumors but drug resistance is a significant clinical challenge.
• Secondary or

Purpose of the Study:

• To investigate the Darwinian selection of secondary BRCA1/2 mutations under PARP inhibitor treatment.
• To explore therapeutic strategies targeting PARP inhibitor-resistant tumors with secondary mutations.

Main Methods:

• CRISPR mutagenesis to create isogenic tumor cell models with secondary BRCA1/2 mutations.
• In vitro and in vivo xenograft experiments to monitor clonal evolution under therapy.
• Assessment of WEE1 kinase inhibitor AZD-1775 efficacy in heterogeneous tumor models.

Main Results:

• PARP inhibitor or platinum salt exposure selects for secondary mutant clones in a Darwinian manner.
• Secondary mutant cells impair the efficacy of clinical PARP inhibitors.
• Both PARP inhibitor-sensitive and resistant BRCA2-mutant cells are sensitive to AZD-1775, which showed greater benefit than olaparib in heterogeneous tumors.

Conclusions:

• PARP inhibitor resistance driven by secondary BRCA mutations can be overcome by targeting WEE1 kinase.
• Despite restored gene function in revertant cells, vulnerabilities exist that can be therapeutically exploited.
• AZD-1775 represents a potential therapeutic avenue for patients with PARP inhibitor-resistant BRCA-mutant cancers.