Overexpression of p16-mediated resistance to CDK4/6 inhibitors in the absence of Rb (Witkiewicz et al., 2011) and low expression of p16 did not rescue the clinical benefit in Rb-positive luminal breast cancer patients in the phase II palbociclib monotherapy trial (DeMichele et al., 2015). The gene discussed is RB1; the disease is breast cancer.