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

• DOI: 10.1111/bph.70037
• Publication Date: 2025-04-08T00:13:59Z
• Authors: Subhankar Bose; Priyanka Saha; Md Tanjim Alam; Bilash Chatterjee; Mrinmoy Sarkar; Amit Kumar Dixit; Deepak Kumar; Rakesh Kumar Pathak; Prem Prakash Trip...; Amit Kumar Srivas...

AbstractBackground and PurposeChemoresistance 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 ApproachThe 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 ResultsWe 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 ImplicationsThese 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.