Synthetic lethality betweenCCNE1amplification and loss ofBRCA1

Abstract

High-grade serous ovarian cancers (HGSCs) are characterized by a high frequency of TP53 mutations, BRCA1/2 inactivation, homologous recombination dysfunction, and widespread copy number changes. Cyclin E1 (CCNE1) gene amplification has been reported to occur independently of BRCA1/2 mutation, and it is associated with primary treatment failure and reduced patient survival. Insensitivity of CCNE1-amplified tumors to platinum cross-linking agents may be partly because of an intact BRCA1/2 pathway. Both BRCA1/2 dysfunction and CCNE1 amplification are known to promote genomic instability and tumor progression. These events may be mutually exclusive, because either change provides a path to tumor development, with no selective advantage to having both mutations. Using data from a genome-wide shRNA synthetic lethal screen, we show that BRCA1 and members of the ubiquitin pathway are selectively required in cancers that harbor CCNE1 amplification. Furthermore, we show specific sensitivity of CCNE1-amplified tumor cells to the proteasome inhibitor bortezomib. These findings provide an explanation for the observed mutual exclusivity of CCNE1 amplification and BRCA1/2 loss in HGSC and suggest a unique therapeutic approach for treatment-resistant CCNE1-amplified tumors.RNAi | pan-cancer | CDK2 | cell cycle | DNA repair E pithelial ovarian cancer is complex and histologically diverse but still largely treated as a single disease with limited stratification based on histological or molecular characteristics. High-grade serous ovarian cancer (HGSC) accounts for the majority of epithelial ovarian cancer-related deaths (>60%), and almost no improvement in survival has been observed in the last 20 y (1). Widespread copy number changes are a hallmark of HGSC, including focal amplification of Cyclin E1 (encoded by CCNE1), which is associated with primary treatment failure (2) and reduced survival (3). Amplification of CCNE1 is one of very few well-defined molecular targets in HGSC.Cyclin E1 forms a complex with cyclin-dependent kinase 2 (CDK2) to regulate G1/S transition as well as having kinase-independent functions, including in DNA replication (4). Ovarian cell lines with CCNE1 amplification show a specific dependency for maintenance of CCNE1 expression (5, 6). We have validated CDK2 as a therapeutic target by showing selective sensitivity to suppression either by gene knockdown or using small molecule inhibitors (7), consistent with findings in breast cancer (8).Recent genomic studies have revealed a high frequency of BRCA1/2 (Breast cancer 1/2, early onset) inactivation and homologous recombination (HR) dysfunction in HGSC (9). Alterations of genes in the HR pathway include germ-line and somatic mutations of BRCA1 or BRCA2 (∼20% of patients) and epigenetic silencing of BRCA1 by hypermethylation (∼10%). Other genes inactivated by deletion, mutation, or hypermethylation include ATM, ATR, RAD51C, and PTEN (∼10%), key Fanconi anemia members (∼5%), and amplification or mutation of EMSY (∼8%). Collectively, at least 50% of HGSCs are...

A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis

“…So far, these patterns have been explained in terms of linear pathways: co-occurring mutations tend to target genes in parallel signaling pathways, whereas mutual exclusive alterations may implicate genes involved either in a common pathway, or in different progression pathways, i.e., in different tumor types (1)(2)(3)(4)(5). Mutual exclusivity could also involve genes that are synthetically lethal (6). These explanations are only hand waving arguments, though.…”

Mechanisms and Targets Involved in Dissemination of Ovarian Cancer

“…We did not discuss approaches based on the mutational status of the EOC of patients such as inducing synthetic lethality with poly ADP ribose polymerase inhibitors in patients with BRCA1 or -2 mutations which are being evaluated in several ongoing clinical studies (152,153). This also holds true for other synthetic lethality-based approaches based on the genetics of the primary tumor (154,155).…”

Achieving Precision Death with Cell-Cycle Inhibitors that Target DNA Replication and Repair

“…Mutations in ATM and ATR have been observed in 2% of HGSOCs, and 5% have mutations in genes of the FA DNA repair pathway (39). Mutually exclusive with mutations in BRCA1 and BRCA2, CCNE1 is amplified in 15% to 20% of HGSOCs (82,84). RB1 loss is also observed in about 15% of these cancers (83).…”