Our data suggest that ovarian cancer cells adapt to CDK inhibition by acquiring, or selecting for, multiple de novo copy number aberrations that are upstream of cyclin D or cyclin E: Copy number gain and overexpression of CCNE1, as well as loss of RB1, was observed in PD0332991-resistant cells, and experimental modulation of cyclin E1 expression altered PD0332991 sensitivity, whereby overexpression of cyclin E1 conferred resistance to CDK4/6 inhibition, whereas genetic depletion of cyclin E1 increased sensitivity to CDK4/6 inhibition. Here, RB1 is linked to ovarian carcinoma.