In vitro studies of HNSCC cell lines harboring NOTCH1 LOF mutations demonstrated sensitivity to PI3K/mTOR inhibitors, resulting in apoptosis and reduced clonogenic growth compared to cell lines with wt NOTCH1. Similarly, PI3K/mTOR inhibition showed markedly increased apoptosis and impaired tumor growth in NOTCH1 mutant HNSCC xenograft models. Here, NOTCH1 is linked to neoplasm.