Low PPP2R2A expression promotes sensitivity to CHK1 inhibition in high-grade serous ovarian cancer.

Abstract

Rationale: High-grade serous ovarian cancer (HGSOC), the most lethal epithelial ovarian cancer subtype, faces persistent challenges despite advances in the therapeutic use of PARP inhibitors. Thus, innovative strategies are urgently needed to improve survival rates for this deadly disease. Checkpoint kinase 1 (CHK1) is pivotal in regulating cell survival during oncogene-induced replication stress (RS). While CHK1 inhibitors (CHK1i's) show promise as monotherapy for ovarian cancer, a crucial biomarker for effective stratification in clinical trials is lacking, hindering efficacy improvement and toxicity reduction. PP2A B55α, encoded by PPP2R2A, is a regulatory subunit of the serine/threonine protein phosphatase 2 (PP2A) that influences CHK1 sensitivity in non-small cell lung cancer (NSCLC). Given the complexity of PP2A B55α function in different types of cancer, here we sought to identify whether PPP2R2A deficiency enhances the sensitivity of HGSOC to CHK1 inhibition. Methods: To determine whether PPP2R2A deficiency affects the sensitivity of HGSOC to CHK1 inhibition, we treated PPP2R2A knockdown (KD) HGSOC cells or HGSOC cells with naturally low PPP2R2A expression with a CHK1 inhibitor, then assessed cell growth in in vitro and in vivo assays. Additionally, we investigated the mechanisms contributing to the increased RS and the enhanced sensitivity to the CHK1 inhibitor in PPP2R2A-KD or deficient cells using various molecular biology assays, including western blotting, immunofluorescence, and DNA fiber assays. Results: Our study suggests that PPP2R2A-KD elevates c-Myc-induced RS via upregulation of replication initiation, rendering HGSOC cells reliant on CHK1 for survival, including those resistant to PARP inhibitors. Conclusion: Combined, these results identify PPP2R2A/PP2A B55α as a potential predictive biomarker for CHK1i sensitivity in HGSOC, as well as suggesting it as a therapeutic target to overcome PARP resistance.