The PI3K/AKT/mTOR signaling pathway in breast cancer: Review of clinical trials and latest advances

Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer mortality in women. As the phosphatidylinositol 3-kinase (PI3K) signaling pathway is involved in a wide range of physiological functions of cells including growth, proliferation, motility, and angiogenesis, any alteration in this axis could induce oncogenic features; therefore, numerous preclinical and clinical studies assessed agents able to inhibit the components of this pathway in BC patients. To the best of our knowledge, this is the first study that analyzed all the registered clinical trials investigating safety and efficacy of the PI3K/AKT/mTOR axis inhibitors in BC. Of note, we found that the trends of PI3K inhibitors in recent years were superior as compared with the inhibitors of either AKT or mTOR. However, most of the trials entering phase III and IV used mTOR inhibitors (majorly Everolimus) followed by PI3K inhibitors (majorly Alpelisib) leading to the FDA approval of these drugs in the BC context. Despite favorable efficacies, our analysis shows that the majority of trials are utilizing PI3K pathway inhibitors in combination with hormone therapy and chemotherapy; implying monotherapy cannot yield huge clinical benefits, at least partly, due to the activation of compensatory mechanisms. To emphasize the beneficial effects of these inhibitors in combined-modal strategies, we also reviewed recent studies which investigated the conjugation of nanocarriers with PI3K inhibitors to reduce harmful toxicities, increase the local concentration, and improve their efficacies in the context of BC therapy. In this comprehensive review, we tried to shed light on the presence of alterations in the phosphatidylinositol 3-kinase (PI3K) axis in patients with breast cancer (BC). It could be inferred that mutated PIK3CA is the most common alteration in BC. Regarding the therapeutic approaches, more studies utilized PI3K inhibitors compared with mTOR and AKT inhibitors, recently. To the best of our knowledge, this is the first study that examined the clinical trials in the context of PI3K/AKT/mTOR inhibitors in BC. We showed that 85% of trials evaluated PI3K/AKT/mTOR inhibitors in the form of combination therapy. Moreover, according to phase III data, Everolimus and Alpelisib were the most promising drugs. Using nanocarriers is a beneficial strategy, yet it is in the initial steps.