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

Edward M. Wolin

Research output: Contribution to journalShort survey

44 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-8
Number of pages8
JournalCancer Letters
Volume335
Issue number1
DOIs
StatePublished - Jul 10 2013
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinase
Neuroendocrine Tumors
Sirolimus
HSP90 Heat-Shock Proteins
Therapeutics
Neuroendocrine Cells
Molecular Chaperones
Receptor Protein-Tyrosine Kinases
Gene Expression
Mutation

Keywords

  • Akt
  • Inhibitor
  • MTOR
  • Neuroendocrine tumors
  • Pancreatic
  • PI3K

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

PI3K/Akt/mTOR pathway inhibitors in the therapy of pancreatic neuroendocrine tumors. / Wolin, Edward M.

In: Cancer Letters, Vol. 335, No. 1, 10.07.2013, p. 1-8.

Research output: Contribution to journalShort survey

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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.",
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