Candidate Markers of Olaparib Response from Genomic Data Analyses of Human Cancer Cell Lines

Abstract

The benefit of PARP inhibitor olaparib in relapsed and advanced high-grade serous ovarian carcinoma (HGSOC) is well established especially in BRCA1/2 mutation carriers. Identification of additional biomarkers can help expand the population of patients most likely to benefit from olaparib treatment. To identify candidate markers of olaparib response we analyzed genomic and in vitro olaparib response data from two independent groups of cancer cell lines. Using pan-cancer cell lines (n = 896) from the Genomics of Drug Sensitivity in Cancer database, we applied linear regression methods to identify statistically significant gene predictors of olaparib response based on mRNA expression. We then analyzed whole exome sequencing and mRNA gene expression data from our collection of 18 HGSOC cell lines previously classified as sensitive, intermediate, or resistant based on in vitro olaparib response for mutations, copy number variation and differential expression of candidate olaparib response genes. We identify genes previously associated with olaparib response (SLFN11, ABCB1), and discover novel candidate olaparib sensitivity genes with known functions including interaction with PARP1 (PUM3, EEF1A1) and involvement in homologous recombination DNA repair (ELP4). Further investigations at experimental and clinical levels are required to validate novel candidates, and ultimately determine their efficacy as potential biomarkers of olaparib sensitivity.

Phase II Study of Olaparib and Temozolomide for Advanced Uterine Leiomyosarcoma (NCI Protocol 10250)

“…SLFN11 has been identified as a determinant of response to DNA damaging agents and response to replication stress with higher levels associated with increased benefit from platinum and PARP inhibitors. 24-29 MGMT repairs DNA damage induced by temozolomide and the absence of MGMT predicts responsiveness to temozolomide in some cancers. Using a Cox proportional hazards model, we found no correlation between PFS and pretreatment levels of SLFN11 (hazard ratio [HR], 0.98 [95% CI, 0.52 to 1.83]; P = .90) or MGMT (HR, 1.12 [95% CI, 0.65 to 1.92]; P = .70) RNA (Appendix Fig A4 [online only]).…”

Multiomics Approach to Understanding Olaparib Resistance and Predicting Drug Response

“…The criteria for selecting nonresponders were based on the classification of cancer types, resulting in the use of cell lines from ten breast cancers, six ovarian cancers, and three colorectal cancers (S1 Appendix Table S1). We included the OV-90 cell line, which was not part of the preclinical evaluation, as it was used in previous studies (33).…”