RB1 and cancer: The main two combinatorial strategies involve growth factors that either activate upstream of the cyclin D-CDK4/6-Rb pathway or pathway members, such as mTOR, PI3K, AKT, RAF and MEK, and enhance the cytostatic effect of CDK4/6 inhibitors or the apoptosis of cancer cells (Cheng et al., 1998; Vora et al., 2014; Goel et al., 2016; Herrera-Abreu et al., 2016; Jansen et al., 2017; Formisano et al., 2019; Alves et al., 2021; Lelliott et al., 2021; Zhao et al., 2021).