Resistance mechanisms to HER2-targeted therapies have been most extensively studied in breast cancer, where key contributors include impaired binding to the HER2 extracellular domain, activating mutations in HER2, overexpression of alternative receptors such as EGFR, HER3, and VEGF, and downstream pathway activation via mutations in the PI3K/AKT/mTOR cascade [163]. The gene discussed is PIK3CA; the disease is breast cancer.