BIOMEDICAL REPORTS 7: 391-399, 2017 Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer (Review) NAOKI KAWAHARA, KENJI OGAWA, MIKA NAGAYASU, MAI KIMURA, YOSHIKAZU SASAKI and HIROSHI KOBAYASHI Department of Obstetrics and Gynecology, Nara Medical University, Nara 634-8522, Japan Received August 18, 2017; Accepted September 14, 2017 DOI: 10.3892/br.2017.990 Abstract. Inhibitors of poly(ADP-ribose) polymerase Contents (PARP) are new types of personalized treatment of relapsed platinum-sensitive ovarian cancer harboring BRCA1/2 1. Introduction mutations. Ovarian clear cell cancer (CCC), a subset of 2. Systematic review of the literature using electronic ovarian cancer, often appears as low-stage disease with search in the PubMed/Medline databases a higher incidence among Japanese. Advanced CCC is 3. Future opportunities in the use of PARP inhibition in CCC highly aggressive with poor patient outcome. The aim of 4. Candidate mutated genes for enhancing the therapeutic the present study was to determine the potential synthetic ratio achieved by PARP inhibitors in CCC (Table IA). lethality gene pairs for PARP inhibitions in patients with 5. Upregulated genes enhancing synthetic lethality of CCC through virtual and biological screenings as well as PARP inhibitors in CCC (Table IB) clinical studies. We conducted a literature review for puta- 6. Synthetic lethal gene partners based on tive PARP sensitivity genes that are associated with the chemo resi stance-related genes in CCC (Table IC) CCC pathophysiology. Previous studies identified a variety 7. Discussion of putative target genes from several pathways associated with DNA damage repair, chromatin remodeling complex, PI3K-AKT-mTOR signaling, Notch signaling, cell cycle 1. Introduction checkpoint signaling, BRCA-associated complex and Fanconi's anemia susceptibility genes that could be used Epithelial ovarian cancer is an advanced and metastatic disease as biomarkers or therapeutic targets for PARP inhibition. at presentation and responsible for over 50% of mortalities BRCA1/2, ATM, ATR, BARD1, CCNE1, CHEK1, CKS1B, worldwide in female genital malignancies (1). The current DNMT1, ERBB2, FGFR2, MRE11A, MYC, NOTCH1 and standard treatment strategy for ovarian cancer is cytoreductive PTEN were considered as candidate genes for synthetic surgery followed by platinum- and taxane-based combination lethality gene partners for PARP interactions. When chemotherapy. Approximately 75% of patients with advanced considering the biological background underlying PARP ovarian cancer ultimately suffer from tumor recurrence with inhibition, we hypothesized that PARP inhibitors would 20% of these patients having resistant disease (1). High rates of be a novel synthetic lethal therapeutic approach for CCC recurrence and low chemosensitivity are the two main factors tumors harboring homologous recombination deficiency that account for poor prognosis of this disease. Epithelial and activating oncogene mutations. The results showed that ovarian cancer is a highly heterogeneous disease characterized the majority of CCC tumors appear to have indicators of by at least two different subtypes, including distinct clinico- DNA repair dysfunction similar to those in BRCA-mutation pathologic characteristics, molecular pathogenesis, responses carriers, suggesting the possible utility of PARP inhibitors to treatment and patient prognosis (2). Each subtype also in a subset of CCC. contains a distinct gene mutation profile and exhibits varied gene expression patterns. Type 1 ovarian cancer includes endometrioid cancer and clear cell cancer (CCC) (so-called endometriosis-associated ovarian cancer). Endometrioid cancer frequently possesses mutations in phosphatase and Correspondence to: Dr Hiroshi Kobayashi, Department of tensin homolog (PTEN), catenin β1 (CTNNB1), phosphati- Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, dylinositol-4,5-bisphosphate 3-kinase catalytic subunit α Nara 634-8522, Japan E-mail: [email protected] (PIK3CA) and AT-rich interaction domain 1A (ARID1A) (3). PIK3CA and ARID1A are also commonly mutated in CCC Key words: synthetic lethality, ovarian clear cell cancer, PARP and this tumor frequently shows hepatocyte nuclear factor-1β inhibitors, replication stress (HNF-1β) overexpression (3). Although Type 1 cancer often appears as low-stage disease, advanced CCC is a cancer that is highly aggressive with poor patient outcome. By contrast, 392 KAWAHARA et al: SYNTHETIC LETHALITY PARTNERS TO PARP INHIBITORS IN OVARIAN CLEAR CELL CANCER Type 2 ovarian cancer includes high-grade serous ovarian to genomic instability requires various DNA repair genes (9). cancer (HGSC), which is the most common histotype of DDR deficiency results in replication stress, commonly induces epithelial ovarian cancer and is characterized by advanced replication fork slowing or stalling and also activates DNA repair stage at onset. HGSC possesses nearly universal mutation checkpoint proteins [ataxia telangiectasia mutated (ATM), ATM- in and dysfunction of (tumor protein p53) TP53 as well as and Rad3-related (ATR), checkpoint kinase 1 (CHEK1)], which frequent germline and somatic BRCA1/2 (BRCA1/2, DNA prevent further DNA damage (10). DDR regulates cell cycle repair associated) mutations, occurring in at least 30% of arrest, which enables DNA repair to occur. PARP1 plays a key tumors (3). role in numerous cell processes including DNA repair, replication Recent advances for the development of efficient personalized and cell death/survival balance (11). PARP1 is mainly involved therapy may lead to the development of successful strategies in the repair of DNA single-strand breaks. Accumulation of for molecular-targeted medicine (small-molecule inhibitors or DNA double-strand breaks (DSBs) is generally repaired by the antibodies), clinical applications of immunotherapy (PD-1 and two DNA DSB repair pathways: Homologous recombination -L1 antibodies) and identification of synthetic lethal partners (4). (HR) and non-homologous end joining (NHEJ). DNA repair Advances in the treatment of HGSC through use of synthetic defects are frequently encountered in human cancers, whereas lethal approaches have also been made. Notably, inhibitors of DNA repair pathways mediated by PARP1 serve as backups (11). [poly(ADP-ribose) polymerase] (PARP) are considered the Approximately 50% of HGSC incur germline or somatic most active and exciting new personalized target therapy for mutations in genes related to HR [BRCA1/2, BRCA paralogs, the treatment of ovarian cancer, especially relapsed platinum- RAD51 (RAD51 recombinase), checkpoint activation genes and sensitive HGSC (5). However, patients without BRCA1/2 Fanconi's anemia genes] and the rest incur genetic alterations in mutations may also benefit from PARP inhibitors, suggesting a mismatch repair (MMR) genes and other genes in the HR/DNA sensitive non-BRCA1/2-mutation subgroup (6). repair pathway at high frequencies (10). The global genome- The prevalence of CCC in Japan reaches up to 15-25% wide mutational landscape revealed that the majority of HGSC compared to those of North America and Europe with a patients harbor the actionable impact of germline and somatic reported prevalence of 1-12% (7,8). CCC showed a different mutations and DNA repair gene defects. HGSC cells harboring genomic expression map from HGSC, which suggested a new HR deficiencies are exceptionally sensitive to PARP inhibi- target therapy (5). Despite many improvements in targeted tion. PARP inhibitors are an effective treatment strategy when therapy for ovarian cancer, exploration of novel synthetic they are used in BRCA1/2-mutated ovarian cancers, which has lethal targets is required in CCC. Investigators have performed led to a shift in the treatment paradigm of this disease (12,13). computational virtual screenings and further experimental The concept of synthetic lethality interactions can be exploited validations to determine whether two-compound formulations in tumors that harbor germline and somatic mutations causing are susceptible to synthetic lethality and may therefore indi- defective DDR/DNA repair (14). Thus, not only BRCA1/2 muta- cate a therapeutic opportunity. tions, but also other HR deficiencies, have been established as a The aim of the present study was to determine the potential targeted therapy (14). synthetic lethality gene partners for PARP inhibitions in CCC Based on a literature search, we initially identified differen- patients through virtual and biological screenings. tially expressed genes and genomic mutations throughout the ovarian cancer between CCC and HGSC, which were 2. Systematic review of the literature using electronic recapitulated in CCC cell lines in vitro, in xenografts in vivo search in the PubMed/Medline databases and in a comprehensive analysis of clinical data (15-21). We then explored virtual and biological screenings against The study aimed to determine the potential synthetic synthetic lethal gene partners of PARP inhibition in ovarian lethality gene partners for PARP inhibitions in patients with cancer. The majority of samples were derived from patients CCC through virtual and biological screenings as well as with HGSC. Of the candidate genes that were likely to be clinical studies. A PubMed (http://www.ncbi.nlm.nih.gov/ synthetic lethal with PARP inhibitors, we selected genes that pubmed) search of the relevant literature published between were frequently mutated, amplified, or upregulated in CCC.