Sir Peter MacCallum Department of Oncology - Research Publications

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End date: 2021 × Author: Au-Yeung, George × Author: Bowtell, David ×

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    Resistance to CDK2 Inhibitors Is Associated with Selection of Polyploid Cells in CCNE1-Amplified Ovarian Cancer
    Etemadmoghadam, D ; Au-Yeung, G ; Wall, M ; Mitchell, C ; Kansara, M ; Loehrer, E ; Batzios, C ; George, J ; Ftouni, S ; Weir, BA ; Carter, S ; Gresshoff, I ; Mileshkin, L ; Rischin, D ; Hahn, WC ; Waring, PM ; Getz, G ; Cullinane, C ; Campbell, LJ ; Bowtell, DD (AMER ASSOC CANCER RESEARCH, 2013-11-01)
    PURPOSE: Amplification of cyclin E1 (CCNE1) is associated with poor outcome in breast, lung, and other solid cancers, and is the most prominent structural variant associated with primary treatment failure in high-grade serous ovarian cancer (HGSC). We have previously shown that CCNE1-amplified tumors show amplicon-dependent sensitivity to CCNE1 suppression. Here, we explore targeting CDK2 as a novel therapeutic strategy in CCNE1-amplified cancers and mechanisms of resistance. EXPERIMENTAL DESIGN: We examined the effect of CDK2 suppression using RNA interference and small-molecule inhibitors in SK-OV-3, OVCAR-4, and OVCAR-3 ovarian cancer cell lines. To identify mechanisms of resistance, we derived multiple, independent resistant sublines of OVCAR-3 to CDK2 inhibitors. Resistant cells were extensively characterized by gene expression and copy number analysis, fluorescence-activated cell sorting profiling and conventional karyotyping. In addition, we explored the relationship between CCNE1 amplification and polyploidy using data from primary tumors. RESULTS: We validate CDK2 as a therapeutic target in CCNE1-amplified cells by showing selective sensitivity to suppression, either by gene knockdown or using small-molecule inhibitors. In addition, we identified two resistance mechanisms, one involving upregulation of CDK2 and another novel mechanism involving selection of polyploid cells from the pretreatment tumor population. Our analysis of genomic data shows that polyploidy is a feature of cancer genomes with CCNE1 amplification. CONCLUSIONS: These findings suggest that cyclinE1/CDK2 is an important therapeutic target in HGSC, but that resistance to CDK2 inhibitors may emerge due to upregulation of CDK2 target protein and through preexisting cellular polyploidy.
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    Synthetic lethality between CCNE1 amplification and loss of BRCA1
    Etemadmoghadam, D ; Weir, BA ; Au-Yeung, G ; Alsop, K ; Mitchell, G ; George, J ; Davis, S ; D'Andrea, AD ; Simpson, K ; Hahn, WC ; Bowtell, DDL (NATL ACAD SCIENCES, 2013-11-26)
    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.