Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors.
BACKGROUND
The precise involvement of the PI3K/mTOR and RAS/MEK pathways in carcinoid tumors is not well defined. Therefore, the purpose of our study was to evaluate the role these pathways play in carcinoid cell proliferation, apoptosis, and secretion and to determine the effects of combined treatment on carcinoid tumor inhibition.


METHODS
The human neuroendocrine cell lines BON (pancreatic carcinoid), NCI-H727 (lung carcinoid), and QGP-1 (somatostatinoma) were treated with either the pan-PI3K inhibitor, BKM120, or the dual PI3K-mTOR inhibitor, BEZ235, alone or in combination with the MEK inhibitor, PD0325901; proliferation, apoptosis, and protein expression were assessed. Peptide secretion was evaluated in BON and QGP-1 cells. The antiproliferative effect of BEZ235, alone or combined with PD0325901, was then tested in vivo.


RESULTS
Both BKM120 and BEZ235 decreased proliferation and increased apoptosis; combination with PD0325901 significantly enhanced the antineoplastic effects of either treatment alone. In contrast, neurotensin peptide secretion was markedly stimulated with BKM120 treatment, but not BEZ235. The combination of BEZ235 + PD0325901 significantly inhibited the growth of BON xenografts without systemic toxicity.


CONCLUSIONS
Both BKM120 and BEZ235 effectively inhibited neuroendocrine tumor (NET) cell proliferation and stimulated apoptosis. However, inhibition of the PI3K pathway alone with BKM120 significantly stimulated neurotensin peptide secretion; this did not occur with the dual inhibition of both PI3K and mTOR using BEZ235 suggesting that this would be a more effective treatment regimen for NETs. Moreover, the combination of BEZ235 and the MEK inhibitor PD0325901 was a safe and more effective therapy in vivo compared with single agents alone.
Authors' Affiliations: Departments of Surgery, Internal Medicine, and Biostatistics; Markey Cancer Center, University of Kentucky, Lexington, Kentucky; and Department of Surgery, University of Texas Medical Branch, Galveston, Texas.
Joseph D
JD
Valentino
Jing
J
Li
Yekaterina Y
YY
Zaytseva
W Conan
WC
Mustain
Victoria A
VA
Elliott
Ji Tae
JT
Kim
Jennifer W
JW
Harris
Katherine
K
Campbell
Heidi
H
Weiss
Chi
C
Wang
Jun
J
Song
Lowell
L
Anthony
Courtney M
CM
Townsend
B Mark
BM
Evers
D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D018358:Neuroendocrine Tumors / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D001549:Benzamides; D004159:Diphenylamine; D007093:Imidazoles; D020928:Mitogen-Activated Protein Kinases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D016283:Proto-Oncogene Proteins p21(ras); D011804:Quinolines; C571178:NVP-BKM120; C506614:mirdametinib; C531198:dactolisib