In summary, we have delineated a major metabolic mechanism explaining resistance to Palbociclib in a colorectal cancer model, namely glutaminolysis-driven OXPHOS, and shown that the combination of a selective CDK4/6 inhibitor with a selective glutaminase inhibitor optimally resensitizes cancer cells to CDK4/6 inhibition through many cell generations. Here, CDK4 is linked to colorectal cancer.