Synthetic lethality between CCNE1 amplification and loss of BRCA1.
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.
Department of Research, Peter MacCallum Cancer Centre, East Melbourne, VIC 3002, Australia.
Dariush
D
Etemadmoghadam
Barbara A
BA
Weir
George
G
Au-Yeung
Kathryn
K
Alsop
Gillian
G
Mitchell
Joshy
J
George
Sally
S
Davis
Alan D
AD
D'Andrea
Kaylene
K
Simpson
William C
WC
Hahn
David D L
DD
Bowtell
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics*; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D019927:Cyclin E / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D059765:Homologous Recombination / Q000187:drug effects; D006801:Humans; D046228:Microarray Analysis; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics
D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D001897:Boronic Acids; C475820:CCNE1 protein, human; D019927:Cyclin E; D015513:Oncogene Proteins; D011719:Pyrazines; D034741:RNA, Small Interfering; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex
CDK2; DNA repair; RNAi; cell cycle; pan-cancer