PI3K/Akt/mTOR pathway inhibitors in the therapy of pancreatic neuroendocrine tumors

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is implicated in the pathogenesis of pancreatic neuroendocrine tumors (pNETs). Activation of this pathway is driven by aberrant tyrosine kinase receptor activities. Mutations in the PI3K/Akt/mTOR pathway occur in 15% of pNETs, and expression of genes of the PI3K/Akt/mTOR pathway is altered in the majority of pNETs. The mTOR inhibitor everolimus has been approved by the FDA for the treatment of pNET, but its efficacy may be limited by its inability to prevent mTORC2-mediated activation of Akt. Specific inhibitors of PI3K, Akt, or other pathway nodes, and their concomitant use with mTOR inhibitors, or agents with dual activity, may be more effective. Preclinical studies demonstrate that inhibitors of the PI3K pathway have antitumor activity in pNET cells, either through direct inhibition of individual pathway nodes or indirect inhibition of molecular chaperones such as heat-shock protein 90. Clinical studies are underway evaluating individual node and dual node inhibitors.

► Dysregulation of the PI3K/Akt/mTOR pathway can occur at multiple nodes in pNETs, providing several potential drug targets.
► PI3K pathway inhibitors target pNETs by direct inhibition of individual pathway nodes, or indirectly by inhibiting HSP90.
► Combination of PI3K and mTOR inhibitors, or agents with dual activity, can overcome limitations of mTOR inhibitors alone.
► Akt inhibitors target pNET cells, and MK-2206 has provided responses in pNET patients, with combination trials ongoing.
► Clinical studies are underway evaluating dual node inhibitors in pNET, including novel agents such as NVP-BEZ235.