Resistance to CDK2 Inhibitors Is Associated with Selection of Polyploid Cells in<i>CCNE1</i>-Amplified Ovarian Cancer

Etemadmoghadam, Dariush; Au-Yeung, George; Wall, Meaghan; Mitchell, Chris; Kansara, Maya; Loehrer, Elizabeth; Batzios, Crisoula; George, Joshy; Ftouni, Sarah; Weir, Barbara A.; Carter, Scott L.; Gresshoff, Irma; Mileshkin, Linda; Rischin, Danny; Hahn, William C.; Waring, Paul; Getz, Gad; Cullinane, Carleen; Campbell, Lynda J.; Bowtell, David D.L.

doi:10.1158/1078-0432.ccr-13-1337

Cited by 100 publications

(82 citation statements)

References 32 publications

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“…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).…”

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confidence: 74%

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Synthetic lethality betweenCCNE1amplification and loss ofBRCA1

Etemadmoghadam

Weir

Au-Yeung

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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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...

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confidence: 74%

“…We have recently shown oncogene addiction to Cyclin E1 and its partner kinase, CDK2, in CCNE1-amplified ovarian tumors (7), suggesting that use of CDK2 inhibitors may be effective in these cancers. In addition to CDK2, Cyclin E1 interacts with CDK1 and CDK3 and has kinase-independent functions (4).…”

Section: Ccne1mentioning

confidence: 99%

Synthetic lethality betweenCCNE1amplification and loss ofBRCA1

Etemadmoghadam

Weir

Au-Yeung

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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195

163

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“…Pelvic high-grade serous carcinoma (HGSC) of either tubo-ovarian or endometrial origin is an aggressive and deadly gynecological malignancy with few available targeted therapies, due in part to the absence of high-frequency oncogenic point mutations in drug target genes (1)(2)(3)(4). Recently, The Cancer Genome Atlas (TCGA) projects have advanced our understanding of the genomic landscape of ovarian and endometrial HGSC and confirmed a prevalence of somatic tumor protein p53 mutations and extensive copy number alterations, such as numerous DNA amplifications and deletions (1,5).…”

Section: Introductionmentioning

confidence: 99%

Amplification of the NSD3‑BRD4‑CHD8 pathway in pelvic high‑grade serous carcinomas of tubo‑ovarian and endometrial origin

Jones

Lin

2017

mol clin onc

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Abstract. Identification of novel therapeutics in pelvic high-grade serous carcinoma (HGSC) has been hampered by a paucity of actionable point mutations in target genes. The aim of the present study was to investigate the extent of amplification of the therapeutically targetable NSD3-CHD8-BRD4 pathway in pelvic HGSC, and to determine whether amplification is associated with worse prognosis. The Cancer Genome Atlas (TCGA) ovarian and endometrial cancer cohorts were retrospectively analyzed via online data-mining tools to test the association of NSD3, CHD8 and BRD4 genomic alterations with survival of pelvic HGSC patients. It was demonstrated that amplification of the NSD3-CHD8-BRD4 pathway in the ovarian HGSC cohort (observed in 18% of the cases, 88/489) was significantly associated with worse overall and progression-free survival compared with non-amplified cases. In addition, amplification of NSD3, CHD8 and BRD4 also occurred in 9% (21/232) of overall endometrial cancer TCGA cases, which was associated with worse overall survival. In the endometrial cancer TCGA cohort, NSD3, CHD8 and BRD4 amplification occurred specifically in the serous carcinoma (25%, 13/53) and 'serous-like' copy number high endometrial carcinoma (33%, 20/60) subgroups, compared with the polymerase e (0%, 0/17), microsatellite instability high (0%, 0/65) or low copy number (1%, 1/90) subgroups. These findings support the hypothesis that amplification of the NSD3-BRD4-CDH8 axis is frequent in pelvic HGSC of both ovarian and endometrial origin, and that this pathway is potentially targetable in a subset of HGSC patients.

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“…The major partner kinase of cyclin E, CDK2, phosphorylates Rb and displaces it from a complex with E2F1, which promotes E2F1-dependent transcription of BRCA1 and other DNA damage repair genes [6, 15]. To date, no drugs directly target cyclin E. Further, indirect targeting of cyclin E with currently available CDK2 inhibitors is limited by the development of chemoresistance that occurs in part through E2F1 upregulation [16, 17]. An alternate and emerging paradigm is to convert HR-proficient tumors to HR-deficient phenotypes by using epigenetic drugs [4, 9].…”

Section: Introductionmentioning

confidence: 99%

Panobinostat sensitizes cyclin E high, homologous recombination-proficient ovarian cancer to olaparib

Wilson

Sarfo-Kantanka

Barrack

et al. 2016

Gynecologic Oncology

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Objective Homologous recombination (HR) proficient ovarian cancers, including CCNE1 (cyclin E)-amplified tumors, are resistant to poly (ADP-ribose) polymerase inhibitors (PARPi). Histone deacetylase inhibitors (HDACi) are effective in overcoming tumor resistance to DNA damaging drugs. Our goal was to determine whether panobinostat, a newly FDA-approved HDACi, can sensitize cyclin E, HR-proficient ovarian cancer cells to the PARPi olaparib. Methods Expression levels of CCNE1 (cyclin E), BRCA1, RAD51 and E2F1 in ovarian tumors and cell lines were extracted from The Cancer Genome Atlas (TCGA) and Broad-Novartis Cancer Cell Line Encyclopedia (CCLE). In HR-proficient ovarian cancer cell line models (OVCAR-3, OVCAR-4, SKOV-3, and UWB1.289 + BRCA1 wild-type), cell growth and viability were assessed by sulforhodamine B and xenograft assays. DNA damage and repair (pH2AX and RAD51 co-localization and DRGFP reporter activity) and apoptosis (cleaved PARP and cleaved caspase-3) were assessed by immunofluorescence and Western blot assays. Results TCGA and CCLE data revealed positive correlations (Spearman) between cyclin E E2F1, and E2F1 gene targets related to DNA repair (BRCA1 and RAD51). Panobinostat downregulated cyclin E and HR repair pathway genes, and reduced HR efficiency in cyclin E-amplified OVCAR-3 cells. Further, panobinostat synergized with olaparib in reducing cell growth and viability in HR-proficient cells. Similar co-operative effects were observed in xenografts, and on pharmacodynamic markers of HR repair, DNA damage and apoptosis. Conclusions These results provide preclinical rationale for using HDACi to reduce HR in cyclin E-overexpressing and other types of HR-proficient ovarian cancer as a means of enhancing PARPi activity.

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Resistance to CDK2 Inhibitors Is Associated with Selection of Polyploid Cells inCCNE1-Amplified Ovarian Cancer

Cited by 100 publications

References 32 publications

Synthetic lethality betweenCCNE1amplification and loss ofBRCA1

Synthetic lethality betweenCCNE1amplification and loss ofBRCA1

Amplification of the NSD3‑BRD4‑CHD8 pathway in pelvic high‑grade serous carcinomas of tubo‑ovarian and endometrial origin

Panobinostat sensitizes cyclin E high, homologous recombination-proficient ovarian cancer to olaparib

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