PI3K-AKT-mTOR inhibitors in breast cancers: From tumor cell signaling to clinical trials.

Breast cancer (BC) is the most common women cancer and second most common cause of cancer death in women. A woman living in the United States has 12.3% lifetime risk of being diagnosed with BC. From the genomics point of view, the most common three subtypes of BC encountered in clinics are HR+, HER2+, and TNBC or basal-like BC. Estrogen receptor (ER) status or HER2 amplification or chemotherapy is not sufficient to understand the underlying mechanisms of disease progression and resistance (de novo or acquire). Although hormonal therapy and HER2-directed therapies have produced a considerable positive outcome in HR+ and HER2+ BC respectively, there are no established targeted agents for TNBC and basal-like BC. While PARP inhibitors have shown promising activity in BRCA-related cancers, its value in the treatment of TNBC remains to be demonstrated. The PI3K-AKT-mTOR signaling pathway plays a crucial role in the initiation and progress in tumorigenesis including breast tumorigenesis and regulates critical cellular functions including survival, proliferation, and metabolism. This article aims to understand the role of PI3K-mTORC1/C2 alterations in determining the clinical outcome in the specific breast cancer subtypes. The understanding of the tumor cell signaling will help us in the decision-making the process for obtaining the treatment modalities towards further advancement of the precision medicine. In this review, we will restrict our discussion to a basic understanding of the biology of subtype-specific BC and several targeted agents under development for the treatment of BC.