Our proof-of-concept experiments were conducted in PDOs harboring mutations in TP53, TTN, FAT1, CDKN2A and CSMD3. Since HNSCC can present with diverse mutation combinations and tumors harboring all these five mutations are uncommon, future studies evaluating the efficacy of the AZD5438 and PD0325901 combination across PDOs with varying mutation profiles will be essential to strengthen the translational relevance of this treatment. The gene discussed is FAT1; the disease is head and neck squamous cell carcinoma.