LAUSR

Simple Summary Breast cancer remains the fourth-leading cause of death worldwide, and therapeutic improvement is warranted. The phosphatidylinositol 3-kinase (PI3K) pathway is one of the major pathways in oncogenesis, and PI3K alterations are common in all breast cancer subtypes. Despite modest clinical activity and a high toxicity rate, pan-PI3K inhibitors paved the way for selective PI3K inhibitor development. In this overview, we cover the past, the present, and potential paths, as well as the therapeutic challenges to come for this therapeutic class. Abstract The phosphatidylinositol 3-kinase (PI3K) pathway is one of the most altered pathways in human cancers, and it plays a central role in cellular growth, survival, metabolism, and cellular mobility, making it a particularly interesting therapeutic target. Recently, pan-inhibitors and then selective p110α subunit inhibitors of PI3K were developed. Breast cancer is the most frequent cancer in women and, despite therapeutic progress in recent years, advanced breast cancers remain incurable and early breast cancers are at risk of relapse. Breast cancer is divided in three molecular subtypes, each with its own molecular biology. However, PI3K mutations are found in all breast cancer subtypes in three main “hotspots”. In this review, we report the results of the most recent and main ongoing studies evaluating pan-PI3K inhibitors and selective PI3K inhibitors in each breast cancer subtype. In addition, we discuss the future of their development, the various potential mechanisms of resistance to these inhibitors and the ways to circumvent them.