Wang Z, et al. - Given that, >80% of head and neck squamous cell carcinomas (HNSCC) involve aberrant activation of the PI3K–mTOR signaling pathway, researchers focused on the role of EIF4E-BP1 (4E-BP1, a direct target of mTOR that serves as a key effector for protein synthesis) in the treatment of HNSCC. Although 4E-BP1 was found to be rarely mutated, over 35% of the patients with HNSCC showed loss of at least one 4E-BP1 gene copy, associating with reduced 4E-BP1 protein expression, in a systematic investigation of genomic changes in the PIK3CA–mTOR pathway in HNSCC. Findings revealed a correlation between 4E-BP1 gene copy number loss and poor disease-free and overall survival. They found that through phosphorylation, 4E-BP1 was persistently restrained by mTOR in HNSCC. They also noted that the tumor-suppressive function of 4E-BP1 could be restored by mTOR inhibitors (mTORi). In patients with HNSCC, 4E-BP1 expression and phosphorylation status were supported as a mechanistic biomarker of mTORi sensitivity.