Cyclin E Modulates Vulnerability to CDC7 Kinase Inhibition

CCNE1 (cyclin E) is frequently amplified or overexpressed in triple negative breast cancer. Cyclin E overexpression enhanced sensitivity to CDC7 inhibition, reducing proliferation and colony forming capacity. Conversely, CCNE1 knockdown rescued proliferation and colony outgrowth in the presence of CDC7 inhibition and reversed accumulation with >=4N DNA content. CRISPR screening revealed cyclin-dependent kinase 8 (CDK8) as conferring resistance to CDC7 inhibition in a CCNE1amplified cell line. Combined CDC7 and CDK8 inhibition significantly reduced proliferation and colony forming ability, led to >=4N DNA content and reduced tumor volume and mass in vivo. This work identifies the enhanced vulnerability of cyclin E-overexpressing TNBC cells to CDC7 kinase inhibition and substantial synergy when combined with CDK8 inhibition.