Given the current clinical trials addressing palbociclib and other CDK4/6 inhibitors for the treatment of HNSCC, these data strongly advocate that homology between COSCC and HNSCC extends far beyond similarities in transcriptional signatures, and allows interrogation of therapeutic vulnerabilities using COSCC as a model for HNSCC, to support translation of novel therapies from bench to bedside. This evidence concerns the gene CDK4 and head and neck squamous cell carcinoma.