title: PI3K/Akt/mTOR pathway inhibitors in the therapy of pancreatic neuroendocrine tumors.
abstract: 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.
authors: Division of Hematology/Oncology, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Los Angeles, CA 90048, USA. edward.wolin@cshs.org
authors: Edward M
authors: EM
authors: Wolin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D000068338:Everolimus; D006801:Humans; D058990:Molecular Targeted Therapy; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000201:enzymology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000068338:Everolimus; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human