Abstract 2773: Homologous recombination deficiency in the CCLE cell lines correlates with in vitro resistance to platinum agents and PARP inhibitors

Abstract

Abstract Background: Since the advent of high-throughput sequencing technologies, multi-omics data along with large-scale drug sensitivity screening data on cancer cell lines from the NCI-60 panel and the CCLE (Cancer Cell Line Encyclopedia) project have been established and widely used for cancer research. Although we previously reported the utility of homologous recombination deficiency (HRD), commonly found in ovarian and breast cancer, as a clinical biomarker across cancer types (PMID:35613413), whether HRD status in cancer cell lines can be an indicator of drug sensitivity to platinum agents or PARP inhibitors has not been fully investigated. Methods: From CCLE publicly available datasets, BRCA1/2 gene mutations and their loss of heterozygosity (LOH) status, HRD score, mutational signature 3 (SBS3), and BRCA1 methylation silencing were analyzed. In vitro drug screening data were obtained from the GDSC (Genomics of Drug Sensitivity in Cancer), CTRP (Cancer Therapeutic Response Portal), and PRISM (Profiling Relative Inhibition Simultaneously in Mixtures) databases. We additionally analyzed anticancer drug response in cell line-derived xenograft models using the dataset of ROADMAPS (Responses to Oncology Agents and Dosing in Models to Aid Preclinical Studies). Results: A total of 1260 cell lines from the CCLE were analyzed. HRD score and SBS3 were positively correlated (ρ=0.36). These scores were higher in samples with BRCA1 methylation and BRCA1/2 mutations involving locus-specific LOH (referred to collectively as BRCA alteration), but not in samples with BRCA1/2 mutations lacking locus-specific LOH. Per-drug correlation analysis between cell line HRD scores and the areas under the drug response curve (AUCs) showed statistically significant (p<0.05) positive correlations in 60% (6/10) of platinum compounds and in 46% (6/13) of PARP inhibitors, but no negative correlations in any of these drugs. A similar trend was observed in the analysis using SBS3 and in the two-group comparison with and without BRCA alteration, indicating that cell lines with HRD were more resistant to platinum agents or PARP inhibitors. In contrast, drug response analysis in xenograft models showed that HRD score and SBS3 were non-significantly higher in cisplatin-high-sensitivity cell lines than those with low sensitivity (median HRD score 45 vs 36, median SBS3 11.7 vs 3.5). Conclusion: When comparing in vitro drug sensitivity among cancer cell lines, HRD correlates with resistance rather than with response to platinum or PARP inhibitors. Thus, the association between HRD status and drug sensitivity of cancer cells is substantially different between tumors in dish culture and in clinical settings. This study provides critical insights that should be considered when using cancer cell lines and underscores the need for experimental models that better reflect efficacy in clinical tumors. Citation Format: Shiro Takamatsu, Noriomi Matsumura. Homologous recombination deficiency in the CCLE cell lines correlates with in vitro resistance to platinum agents and PARP inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2773.