Cyclin E1 Amplification Confers Sensitivity to Proteasome Inhibition

Amplification of Cyclin E1 (CCNE1) is common in high-grade serous ovarian cancer and is associated with poor outcome. CCNE1 amplification has been observed to be mutually exclusive of the BRCA1/2 mutations frequently found in ovarian cancer, suggesting that CCNE1-amplified tumors may be insensitive to platinum cross-linking agents or PARP inhibitors because they have an intact homologous recombination pathway. Etemadmoghadam and colleagues queried The Cancer Genome Atlas and found that CCNE1 was amplified in approximately 25% of high-grade serous ovarian cancers as well as 5% of breast, gastric, and lung cancers. Moreover, the authors validated the mutual exclusivity between high-level CCNE1 amplification (approximately 8 copies per genome) and germline BRCA1/2 mutation using data from the Australian Ovarian Cancer Study. To identify essential genes in CCNE1-amplified cells that might encode potential therapeutic targets, the authors analyzed data from the Project Achilles genome-wide shRNA screen involving 102 ovarian cancer cell lines. In addition to CCNE1 itself and the gene encoding its binding partner cyclin-dependent kinase 2 (CDK2), BRCA1 and genes encoding multiple components of the ubiquitin pathway were identified and validated as specifically required for survival of CCNE1-amplified cell lines. In addition to providing an explanation for the mutual exclusivity between CCNE1 amplification and BRCA1 loss, these dependencies suggested that CCNE1-amplified cells may be especially sensitive to proteasome inhibition, given that proteasome activity requires ubiquitin pathway components and is necessary for efficient homologous recombination. Indeed, in a panel of ovarian cancer cell lines, those with CCNE1 amplification or overexpression were the most sensitive to the proteasome inhibitor bortezomib, including CCNE1-amplified cell lines that were resistant to CDK2-specific inhibitors. Although bortezomib has not shown activity in unselected patients with ovarian cancer, these findings provide a rationale for evaluation of bortezomib or other proteasome inhibitors in patients with CCNE1-amplified tumors.

Etemadmoghadam D, Weir BA, Au-Yeung G, Aslop K, Mitchell G, George J, et al. Synthetic lethality between CCNE1 amplification and loss of BRCA1. Proc Natl Acad Sci U S A 2013 Nov 11 [Epub ahead of print].