Clinical trials with palbociclib clearly show that some patients do not benefit from CDK4/6 inhibitors.2–4,36 Loss of RB1 has been already suggested as a mechanism of de novo resistance to these drugs.15–19 Here, we identified CCNE1 as an additional potential marker of de novo resistance in a large panel of pan-cancer and BC cell lines. The gene discussed is CDK4; the disease is cancer.