RB1 and breast carcinoma: Notably, combination treatment of MCF7 and MDA-MB-231 cells with D 4476 and ribociclib not only protected RB1 from degradation, but also abolished CDK6 accumulation (Fig. 3i), indicating that the combination of D 4476 and ribociclib may prevent breast cancer cells from acquisition of CDK4/6i resistance by at least two mechanisms, namely preventing degradation of RB1 and accumulation of CDK6, respectively.