Homologous Recombination Deficiency Unrelated to Platinum and PARP Inhibitor Response in Cell Line Libraries

Abstract

While large publicly available cancer cell line databases are invaluable for preclinical drug discovery and biomarker development, the association between homologous recombination deficiency (HRD) and drug sensitivity in these resources remains unclear. In this study, we comprehensively analyzed molecular profiles and drug screening data from the Cancer Cell Line Encyclopedia. Unexpectedly, gene alterations in BRCA1/2 or homologous recombination-related genes, HRD scores, or mutational signature 3 were not positively correlated with sensitivity to platinum agents or PARP inhibitors. Rather, higher HRD scores and mutational signature 3 were significantly associated with resistance to these agents in multiple assays. These findings were consistent when analyzing exclusively breast and ovarian cancer cell lines and when using data from the COSMIC Cell Line Project. Collectively, the existing data from established cancer cell lines do not reflect the expected association between HRD status and drug response to platinum agents and PARP inhibitors in clinical tumors. This discrepancy may extend to other tumor characteristics, highlighting the importance of recognizing potential limitations in cell line data for researchers.