CCNE1 encodes cyclin E1, a critical regulator of the G1/S cell cycle transition that functions as a regulatory subunit of cyclin-dependent kinase 2 (CDK2) 1. In normal cells, CCNE1 controls entry into S phase through protein phosphorylation and positive regulation of G1/S transition 1. However, CCNE1 amplification is prevalent in multiple cancer types, particularly high-grade serous ovarian cancer (20%), endometrial cancer (45.4%), and gastro-oesophageal cancers, where elevated cyclin E1 levels associate with genome instability, whole-genome doubling, and chemotherapy resistance 2 3. Mechanistically, elevated CCNE1 expression induces replicative stress that activates ATR-Chk1-dependent checkpoints; p53 subsequently promotes mitotic bypass and endoreduplication, facilitating whole-genome duplication in cancer evolution 4. CCNE1 amplification confers resistance to CDK4/6 inhibitors like palbociclib, with high CCNE1 expression reducing progression-free survival benefit 5. Therapeutically, CCNE1-amplified tumors show synthetic lethality with PKMYT1 kinase inhibition (RP-6306), and combined targeting of PKMYT1 and ATR achieves durable tumor regression 2 6. CCNE1 status assessment via fluorescence in situ hybridization and immunohistochemistry predicts response to CDK and Wee1 inhibitors, with objective response rates of 32-40% 7. CDK2-selective degraders co-depleting cyclin E1 show promise in CCNE1-amplified cancers 8.