The present study described for the first time the in vivo activity of a CDK4/6 inhibitor and a PLK1 inhibitor in two human chordoma xenografts harboring homozygous deletions of CDKN2A/2B. We also hypothesized that OxPhos activity could lead to as a resistance mechanism to CDK4/6 inhibitors in chordomas. This evidence concerns the gene CDKN2A and chordoma.