A multi‐RTK inhibitor named ponatinib, which targets Ephs, TRKs and c‐Kit, completely eliminated CSC population in vitro and significantly reduced lung metastasis in vivo, suggesting that targeting these RTKs by ponatinib may be an effective therapeutic strategy targeting CSCs in HNSCC with PIK3CA amplification. Here, PIK3CA is linked to head and neck squamous cell carcinoma.