Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 48, Pages 19489-19494Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1314302110
Keywords
RNAi; pan-cancer; CDK2; cell cycle; DNA repair
Categories
Funding
- National Health and Medical Research Council (NHMRC) [APP 1042358]
- Cancer Australia Grant [APP 1004673]
- US National Institutes of Health [U01 CA176058]
- US Army Medical Research and Materiel Command [DAMD17-01-1-0729]
- Cancer Council Tasmania
- NHMRC Grant [ID400413]
- Australian Government's Education Investment Fund through the Super Science Initiative
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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.
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