Therefore, co-targeting the CDK4/6 and PI3K/AKT/mTOR signaling pathways might become a novel promising therapeutic strategy for chordoma patients and might be of enhanced value in the subgroup of PTEN−/p16− chordomas; however, in order to translate these results towards clinical trials, preclinical evidence should be further substantiated by in vivo studies. This evidence concerns the gene PIK3CA and chordoma.