Dual inhibition of PI3K and mTOR signaling pathways decreases human pancreatic neuroendocrine tumor metastatic progression

Clarisse Djukom, Laura J. Porro, Amy Mrazek, Courtney Townsend, Mark Hellmich, Celia Chao

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

OBJECTIVES: Patients with advanced pancreatic neuroendocrine tumors have limited therapeutic options. Everolimus (RAD001), an inhibitor of the mammalian target of rapamycin (mTOR) pathway, has been shown to increase progression-free survival, but not overall survival, indicating a need to identify additional therapeutic targets. Inhibition of mTOR complex 1 by RAD001 may induce upstream AKT upregulation. We hypothesized that dual inhibition of AKT along with mTOR will overcome the limited activity of RAD001 alone. METHODS: The BON cell line has been used as a model to study pancreatic neuroendocrine tumor cell biology. Western blots and cell growth assays were performed with mTOR inhibitor RAD001 (50 nM), mitogen-activated protein kinase inhibitor PD0325901 (50 nM), PI3K (phosphatidylinositol 3-kinase) inhibitor LY294002 (25 μM), or vehicle control. Nude mice were treated daily for 6 weeks with RAD001 (oral gavage) and with LY29400 (subcutaneous) 1 week after intrasplenic injection of BON cells. RESULTS: Cellular proliferation was most attenuated with the combination therapy of LY29400 and RAD001. Similarly, the volume of liver metastasis was lowest in the group treated with both LY29400 (100 mg/kg per week, subcutaneous) and RAD001 (2.5 mg/kg per day) compared with that in the vehicle group (P = 0.04). CONCLUSION: The combination therapy of LY29400 and RAD001 decreased the cell growth in vitro and progression of liver metastasis in vivo compared with vehicle or with single-drug therapy.

Original languageEnglish (US)
Pages (from-to)88-92
Number of pages5
JournalPancreas
Volume43
Issue number1
DOIs
StatePublished - Jan 2014

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Phosphatidylinositol 3-Kinase
Neuroendocrine Tumors
Sirolimus
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Neoplasm Metastasis
Everolimus
Neuroendocrine Cells
Liver
Therapeutics
Protein Kinase Inhibitors
Growth
Mitogen-Activated Protein Kinases
Nude Mice
Disease-Free Survival
Cell Biology
Up-Regulation
Western Blotting
Cell Proliferation
Drug Therapy

Keywords

  • BON cell
  • liver metastasis
  • pancreatic neuroendocrine tumor
  • RAD001

ASJC Scopus subject areas

  • Hepatology
  • Internal Medicine
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Dual inhibition of PI3K and mTOR signaling pathways decreases human pancreatic neuroendocrine tumor metastatic progression. / Djukom, Clarisse; Porro, Laura J.; Mrazek, Amy; Townsend, Courtney; Hellmich, Mark; Chao, Celia.

In: Pancreas, Vol. 43, No. 1, 01.2014, p. 88-92.

Research output: Contribution to journalArticle

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