Chapter 4 - An insight on PI3K/AKT/MTOR inhibitors in cancer: Opportunity and translational perspectives

Abstract

Many signaling pathways like the RAS-RAF-MEK-ERK pathway, TGFβ signaling, p53, and β-catenin/Wnt signaling, etc. are activated in tumor cells. Compared with the others, the Phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling has more complicated components. It is regarded as a master regulator in cancer progression. It regulates signal transduction for cell growth, proliferation, survival, motility, differentiation, angiogenesis, apoptosis, innate immunity, and metabolism. Hyper/altered activity of PI3K/AKT/mTOR has been reported in renal cell carcinoma, pancreatic carcinoma, breast neoplasm, chronic lymphocytic leukemia, gastrointestinal stromal tumor, small lymphocytic lymphoma, neuroblastoma, glioblastoma, etc. In recent decades, extensive efforts have been made to develop agents targeting PI3K/AKT/mTOR pathways. Many clinical trials have also been carried out on novel PI3K/AKT/mTOR inhibitors such as BELLE-2 (2019), BELLE-3 (2017), PEGGY (2015), FERGI (2016), BELLE-4 (2015), and BOLERO-2 (2014). Similarly, many clinical trials are going on, like SANDPIPER, SOLAR-1, etc., which show the significance of PI3K/AKT/mTOR inhibitors alone or as a part of multidrug therapy. US-FDA has recently approved PI3K/AKT/mTOR inhibitor Alpelisib (2019) for metastatic breast cancer. This chapter summarizes the significance of PI3K/AKT/mTOR in cancer progression and outlines the mechanism of PI3K/AKT/mTOR inhibition and recent clinical advancements of anticancer drug development in this area.