Abstract
Simple SummaryOlaparib is an oral medication typically used to treat certain advanced ovarian and breast cancers with mutations in BRCA1 or BRCA2 genes. Mutations in these genes can increase the risk of developing breast, ovarian, and other types of cancer. Olaparib is the first clinically approved drug that specifically targets a vulnerability of cancers with these mutations. Genetic alterations in cancer tumors can affect response to treatment in cancer patients. Cancer models such as cell lines, which are cancer cells derived from patients and have been grown in the laboratory over time, can be used to identify these alterations which may contribute to sensitivity or resistance to treatment. We analyzed data from two independent groups of cancer cell lines and identified alterations in additional genes (PUM3, EEF1A1 and ELP4) that potentially increase sensitivity to olaparib. Further experimental and clinical investigations are required to validate our findings.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.
Highlights
IntroductionInhibitor to be clinically approved as maintenance therapy for treatment of advanced or recurrent ovarian cancer
Olaparib is the first poly(adenosine diphosphate[ADP]-ribose) polymerase (PARP)inhibitor to be clinically approved as maintenance therapy for treatment of advanced or recurrent ovarian cancer
The antitumor activity of olaparib is based on the synthetic lethality relationship between PARP and BRCA1/2 where loss of BRCA1/2 function or PARP inhibition alone is compatible with cell survival, but the combination of BRCA1/2 inactivation and PARP inhibition leads to cell death [1]
Summary
Inhibitor to be clinically approved as maintenance therapy for treatment of advanced or recurrent ovarian cancer. It inhibits PARP1 and PARP2 which are involved in the base excision repair (BER) pathway important for repair of damaged bases and single-strand. Olaparib and other PARP inhibitors (PARPis) are especially cytotoxic to BRCA1/2-mutated, homologous recombination (HR) DNA repair deficient, tumor cells by blocking PARP-mediated DNA repair and promoting DNA replication stress through trapped PARP-DNA complexes leading to chromosomal instability, cell cycle arrest and apoptosis [2,3,4]. PARP inhibitors have emerged as promising maintenance therapy for patients with BRCA1/2-mutated HGSOC who were initially sensitive to platinum-based chemotherapy (PBC). BRCA1/2 mutations and alterations in other genes that sensitize tumors to PBC sensitize tumors to PARP inhibitors, as we have recently reviewed [13]
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