Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress

Simple Summary Most gastrointestinal stromal tumors (GISTs) arise due to gain-of-function mutations of KIT and PDGFRA, encoding the receptor tyrosine kinase (RTK). The introduction of the RTK inhibitor imatinib has significantly improved the management of GISTs; however, drug resistance remains a challenge. Constitutive autophosphorylation of RTKs is associated with the activation of the PI3K/AKT/mTOR pathway. Especially, this pathway plays a pivotal role in mRNA translation initiation, directly regulated by eukaryotic initiation factors (eIFs). This review highlights the progress for targeting PI3K/AKT/mTOR-dependent mechanisms in GISTs and explores the relationship between mTOR downstream eIFs and the development of GISTs, which may be a promising future therapeutic target for this tumor entity. Gastrointestinal stromal tumor (GIST) originates from interstitial cells of Cajal (ICCs) in the myenteric plexus of the gastrointestinal tract. Most GISTs arise due to mutations of KIT and PDGFRA gene activation, encoding the receptor tyrosine kinase (RTK). The clinical use of the RTK inhibitor imatinib has significantly improved the management of GIST patients; however, imatinib resistance remains a challenge. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical survival pathway for cell proliferation, apoptosis, autophagy and translation in neoplasms. Constitutive autophosphorylation of RTKs has an impact on the activation of the PI3K/AKT/mTOR pathway. In several preclinical and early-stage clinical trials PI3K/AKT/mTOR signaling inhibition has been considered as a promising targeted therapy strategy for GISTs. Various inhibitory drugs targeting different parts of the PI3K/AKT/mTOR pathway are currently being investigated in phase Iota and phase Iota Iota clinical trials. This review highlights the progress for PI3K/AKT/mTOR-dependent mechanisms in GISTs, and explores the relationship between mTOR downstream signals, in particular, eukaryotic initiation factors (eIFs) and the development of GISTs, which may be instrumental for identifying novel therapeutic targets.