Cyclin E1 as a driver of oncogenesis; high grade serous ovarian cancer as an exemplar
Cyclin E1 is a critical mediator of cell cycle dynamics, controlling G1/S phase transition in complex with CDK2. Overexpression of cyclin E1 can lead to replication stress, DNA damage, and heightened genomic instability. This is associated with oncogenesis, and is frequently observed pan-cancer; but is particularly common in high grade serous ovarian cancer (HGSOC). HGSOC exhibits a genomic landscape dominated by structural variation and instability, with high cyclin E1 expression in up to 58 % and CCNE1 amplification in up to 30 % of cases. HGSOC therefore represents an exemplar setting for investigating cyclin E dysregulation in cancer. HGSOC patients with high tumour expression of cyclin E1, in combination with copy number amplification, experience particularly poor survival. Agents targeting CDK2, WEE1, and PYMKT1, and other cell cycle associated targets have shown strong preclinical activity in models of high cyclin E expression and CCNE1 amplification. Recent clinical trials have explored the efficacy and tolerability of these agents, particularly in biomarker selected cohorts. The WEE1 inhibitor adavosertib and the CDK2 inhibitor INCB123667 achieved response rates of 53 % and 33 % respectively in platinum-resistant ovarian cancer patients whose tumours overexpressed cyclin E1. Targeting of cyclin E dysregulation via a synthetic lethality approach is therefore a key area of focus for improving treatment strategies in HGSOC and other cancers with high unmet clinical need. In this review we discuss the functions of cyclin E1, mechanisms and consequences of dysregulation, and strategies for therapeutic exploitation of cyclin E1 dysregulated tumours, combining fundamental biology with clinical perspectives.
