Search for a command to run...
Breast cancer is one of the deadliest cancers that occurs in women.It remains the most invasive and common cancer among women worldwide.In 2023, over 2.3 million new cases were reported, resulting in approximately 685,000 deaths globally. 1,2Despite early detection and current treatment options such as surgery, radiation therapy, chemotherapy, hormone-blocking therapy, targeted therapy, and immunotherapy, breast cancer remains the leading cause of cancer-related death in women. 3-6Breast cancer arises from several gene mutations.A significant percentage of breast cancers involve mutations in the phosphatidylinositol-3 kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT)/mammalian target of rapamycin (mTOR) pathway.Several PI3K inhibitors have been approved for treating various diseases.Alpelisib is currently the only selective PI3K inhibitor targeting breast cancer approved by the U.S. Food and Drug Administration (FDA); however, it is associated with several severe treatment-related adverse events.Several biological processes, such as cell growth and proliferation, cell survival, protein synthesis, and glycolytic metabolism, are regulated by the PI3K/AKT/mTOR signaling cascade. 7,8PI3K is a class of lipid kinases composed of two subunits: the regulatory p85 and catalytic p110. 9The hyperactivation of this pathway induces and supports tumor growth. 10,11Class I PI3K has four isoforms: , , , and .Among these, PI3K is frequently overexpressed in cancer cells through gene amplification or mutation of the PIK3CA gene. 7,11-13Indeed, PI3K hyperactivation occurs in approximately 29% of all breast cancers and 40% of hormone receptor (HR)+/ human epidermal growth factor receptor 2 (HER2)breast cancer.The most common PIK3CA gene mutations are E545K and H1047R, with H1047R located in the catalytic region.Therefore, isoform-selective small-molecule PI3K inhibitors have gained significant interest in drug discovery for cancer treatment.Nevertheless, preclinical studies have demonstrated some drawbacks of PI3K pathway inhibition.The inhibition of PI3K signaling releases negative feedback, leading to activation of receptor tyrosine kinase signaling.This reactivation reengages the pathway, reducing drug efficacy.Additionally, most approved PI3K inhibi-