Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors

Joseph D. Valentino, Jing Li, Yekaterina Y. Zaytseva, W. Conan Mustain, Victoria A. Elliott, Ji Tae Kim, Jennifer W. Harris, Katherine Campbell, Heidi Weiss, Chi Wang, Jun Song, Lowell Anthony, Courtney Townsend, B. Mark Evers

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1212-1222
Number of pages11
JournalClinical Cancer Research
Volume20
Issue number5
DOIs
StatePublished - 2014

Fingerprint

Neuroendocrine Tumors
Phosphatidylinositol 3-Kinases
Carcinoid Tumor
Mitogen-Activated Protein Kinase Kinases
Apoptosis
Neuroendocrine Cells
Neurotensin
Peptides
Somatostatinoma
Cell Proliferation
dactolisib
Heterografts
Antineoplastic Agents
NVP-BKM120
PD 0325901
Cell Line
Lung
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Valentino, J. D., Li, J., Zaytseva, Y. Y., Mustain, W. C., Elliott, V. A., Kim, J. T., ... Evers, B. M. (2014). Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors. Clinical Cancer Research, 20(5), 1212-1222. https://doi.org/10.1158/1078-0432.CCR-13-1897

Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors. / Valentino, Joseph D.; Li, Jing; Zaytseva, Yekaterina Y.; Mustain, W. Conan; Elliott, Victoria A.; Kim, Ji Tae; Harris, Jennifer W.; Campbell, Katherine; Weiss, Heidi; Wang, Chi; Song, Jun; Anthony, Lowell; Townsend, Courtney; Evers, B. Mark.

In: Clinical Cancer Research, Vol. 20, No. 5, 2014, p. 1212-1222.

Research output: Contribution to journalArticle

Valentino, JD, Li, J, Zaytseva, YY, Mustain, WC, Elliott, VA, Kim, JT, Harris, JW, Campbell, K, Weiss, H, Wang, C, Song, J, Anthony, L, Townsend, C & Evers, BM 2014, 'Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors', Clinical Cancer Research, vol. 20, no. 5, pp. 1212-1222. https://doi.org/10.1158/1078-0432.CCR-13-1897
Valentino, Joseph D. ; Li, Jing ; Zaytseva, Yekaterina Y. ; Mustain, W. Conan ; Elliott, Victoria A. ; Kim, Ji Tae ; Harris, Jennifer W. ; Campbell, Katherine ; Weiss, Heidi ; Wang, Chi ; Song, Jun ; Anthony, Lowell ; Townsend, Courtney ; Evers, B. Mark. / Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 5. pp. 1212-1222.
@article{856ac7e7dae64337a4488fb4022d05f6,
title = "Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors",
abstract = "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.",
author = "Valentino, {Joseph D.} and Jing Li and Zaytseva, {Yekaterina Y.} and Mustain, {W. Conan} and Elliott, {Victoria A.} and Kim, {Ji Tae} and Harris, {Jennifer W.} and Katherine Campbell and Heidi Weiss and Chi Wang and Jun Song and Lowell Anthony and Courtney Townsend and Evers, {B. Mark}",
year = "2014",
doi = "10.1158/1078-0432.CCR-13-1897",
language = "English (US)",
volume = "20",
pages = "1212--1222",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "5",

}

TY - JOUR

T1 - Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors

AU - Valentino, Joseph D.

AU - Li, Jing

AU - Zaytseva, Yekaterina Y.

AU - Mustain, W. Conan

AU - Elliott, Victoria A.

AU - Kim, Ji Tae

AU - Harris, Jennifer W.

AU - Campbell, Katherine

AU - Weiss, Heidi

AU - Wang, Chi

AU - Song, Jun

AU - Anthony, Lowell

AU - Townsend, Courtney

AU - Evers, B. Mark

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84895787003&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84895787003&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-13-1897

DO - 10.1158/1078-0432.CCR-13-1897

M3 - Article

VL - 20

SP - 1212

EP - 1222

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 5

ER -