The Biological Roles and Clinical Applications of the PI3K/AKT Pathway in Targeted Therapy Resistance in HER2-Positive Breast Cancer: A Comprehensive Review.

Epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) is a highly invasive and malignant type of tumor. Due to its resistance to HER2-targeted therapy, HER2+ BC has a poor prognosis and a tendency for metastasis. Understanding the mechanisms underlying this resistance and developing effective treatments for HER2+ BC are major research challenges. The phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, which is frequently altered in cancers, plays a critical role in cellular proliferation and drug resistance. This signaling pathway activates various downstream pathways and exhibits complex interactions with other signaling networks. Given the significance of the PI3K/AKT pathway in HER2+ BC, several targeted drugs are currently in development. Multiple drugs have entered clinical trials or gained market approval, bringing new hope for HER2+ BC therapy. However, new drugs and therapies raise concerns related to safety, regulation, and ethics. Populations of different races and disease statuses exhibit varying responses to treatments. Therefore, in this review, we summarize current knowledge on the alteration and biological roles of the PI3K/AKT pathway, as well as its clinical applications and perspectives, providing new insights for advancing targeted therapies in HER2+ BC.