In a third study focused on PI3K pathway combinations, synergy was noted with both the mTOR kinase inhibitor TAK-228 (sapanisertib) and the PI3Ka inhibitor BYL-719 (alpelisib), including in HRAS or PIK3CA mutant (20% of HNSCC) [67], PIK3CA-amplified (15%) [68] or HRAS-overexpressing (30%) (Figure 3) models, and this combination has previously been shown to be synergistic in CDX systems [69], suggesting that simultaneous blockade of these two prominent oncogenic pathways could offer potential benefit in a broad population of HNSCC patients. Here, PIK3CA is linked to head and neck squamous cell carcinoma.