PI3K-dependent activation of non-canonical cyclin D1-CDK2 and resultant recovery of Rb phosphorylation and S phase entry has been implicated in early resistance to CDK4/6 inhibition, with combined PI3K and CDK4/6 inhibition demonstrating the ability to overcome resistance to CDK4/6 inhibitors in BC cell lines (27). This evidence concerns the gene CCND1 and breast cancer.