The reasons for this resistance are manifold, such as up-regulation of HER2 expression, abnormal activation of HER2 downstream signaling pathways, deletion of tumor suppressor genes, cell cycle dysregulation, low infiltration of tumor immune cells, etc. Selective inhibitors of PI3K, inhibition of the IGF1R signaling pathway, and CDK inhibitors can sensitize HER2-positive breast cancer to anti-HER2 therapy, but these therapies have not yet been approved by the FDA and are still in clinical trials. The gene discussed is ERBB2; the disease is neoplasm.