PPP2R1A mutations cause ATR inhibitor sensitivity in ovarian clear cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Synthetic lethality between ARID1A and ATR pathway provides a therapeutic strategy for ovarian clear cell carcinoma (OCCC).
• ATR inhibitors (ATRi) are under investigation for OCCC, but patient stratification is needed.

Purpose of the Study:

• To identify genetic alterations that sensitize ARID1A-mutant OCCC to ATR inhibitors.
• To evaluate the role of protein phosphatase 2A (PP2A) in ATRi sensitivity.
• To assess PPP2R1A mutations as a predictive biomarker for ATRi therapy in OCCC.

Main Methods:

• CRISPR-Cas9 mutagenesis and interference screens were employed to identify genetic modifiers of ATRi sensitivity.
• Analysis of a new OCCC patient cohort for ARID1A and PPP2R1A mutations.
• CRISPR-prime editing was used to create isogenic models of PPP2R1A-mutant OCCC.
• Assessment of ATRi-induced cellular stress, genomic instability, and sensitivity in preclinical models.

Main Results:

• Inactivation of PP2A subunits, including PPP2R1A, enhances ATRi sensitivity in ARID1A-mutant OCCC.
• Approximately 52% of OCCC patients harbor oncogenic PPP2R1A p.R183 mutations, with half of these also having ARID1A mutations.
• PPP2R1A p.R183 mutations (W and P variants) induce ATRi-mediated S phase stress, mitotic entry defects, and genomic instability.
• PPP2R1A p.R183 mutations enhance both in vitro and in vivo ATRi sensitivity in ARID1A-mutant OCCC models.

Conclusions:

• PP2A inactivation, specifically PPP2R1A mutations, confers sensitivity to ATR inhibitors in OCCC.
• PPP2R1A p.R183 mutations are prevalent in OCCC and are associated with enhanced ATRi sensitivity.
• PPP2R1A mutation status should be evaluated as a potential biomarker for predicting ATRi response in OCCC patients.