Inhibition of DNA polymerase eta‐mediated translesion DNA synthesis with small molecule sensitises ovarian cancer stem‐like cells to chemotherapy

BACKGROUND AND PURPOSE: Chemoresistance and tumour relapse pose significant challenges in achieving successful chemotherapy outcomes. Targeting DNA polymerase eta (Pol ƞ)-mediated mutagenic translesion DNA synthesis (TLS) has emerged as a promising strategy for improving chemotherapy. However, the identification of small molecule inhibitors targeting Pol ƞ -mediated TLS with high in vivo efficacy remains a challenge. EXPERIMENTAL APPROACH: The small molecule was identified through in silico screening. Pol η inhibitory potential of the identified small molecule was validated by a fluorescent-based reporter strand displacement assay. Flow cytometry was conducted to analyse the CD44 + CD117 + cancer stem-like cell (CSC) population and live-dead cell population. Xenograft mouse models were used to test the CSC sensitising potential. KEY RESULTS: We screened and identified chrysin as a small-molecule inhibitor that sensitises ovarian cancer stem-like cells to cisplatin treatment by inhibiting Pol ƞ -mediated TLS. Chrysin effectively inhibits Pol ƞ expression, mitigates cancer stem-like cell enrichment and enhances cisplatin-induced cell death both in vitro and in vivo. Furthermore, chrysin treatment reduces spontaneous and cisplatin-induced mutagenesis. Pre-treatment with chrysin attenuates cisplatin-induced haematological toxicity and suppresses tumour growth in human ovarian cancer xenografts. CONCLUSIONS AND IMPLICATIONS: These results establish chrysin as a novel class of TLS inhibitors and highlight its potential as a chemotherapy adjuvant for overcoming chemoresistance and improving treatment outcomes in ovarian cancer.