Exploring novel therapeutic targets in GIST: focus on the PI3K/Akt/mTOR pathway.

Gastrointestinal stromal tumors (GISTs) are the most common soft tissue sarcoma, and most feature abnormalities in two genes encoding the receptor tyrosine kinases (RTKs), KIT, and PDGFRA. The RTK inhibitor imatinib revolutionized treatment in GIST; however, drug resistance remains a challenge. Constitutive autophosphorylation of RTKs is linked to phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway hyperactivation, which is central to oncogenic signaling, and known to be dysregulated in GIST. Preclinical experiments have confirmed that inhibiting the PI3K/Akt/mTOR pathway is a rational target for therapy. Early studies using mTOR inhibitors have shown limited success, which may be due to the activation of Akt that occurs following mTORC1 inhibition. Therefore, targeting PI3K or Akt, which lie upstream of mTORC1, may translate into more complete pathway inhibition. Several treatment strategies are currently being developed in phase 1 and 2 clinical trials. Compounds currently in development include pan-Class I PI3K inhibitors, dual PI3K/mTOR inhibitors, and Akt inhibitors. The aim of this review is to highlight the evidence for targeting PI3K/Akt/mTOR-dependent mechanisms in GIST and to evaluate the existing preclinical and clinical data supporting this strategy.