Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models

Patients with pancreatic cancer have dismal prognoses, and novel therapies are urgently needed. Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target. Direct targeting of the predominant KRAS pathways have been challenging and research into therapeut...

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Main Authors:	Zhong, Hua, Sanchez, Cesar, Spitrzer, Dirk, Plambeck-Suess, Stacy, Gibbs, Jesse, Hawkins, Williams G., Denardo, David, Gao, Feng, Pufahl, Robert A., Lockhart, Albert C., Xu, Mai, Linehan, David, Weber, Jason, Wang-Gillam, Andrea
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793961/

id	pubmed-3793961
recordtype	oai_dc
spelling	pubmed-37939612013-10-15 Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models Zhong, Hua Sanchez, Cesar Spitrzer, Dirk Plambeck-Suess, Stacy Gibbs, Jesse Hawkins, Williams G. Denardo, David Gao, Feng Pufahl, Robert A. Lockhart, Albert C. Xu, Mai Linehan, David Weber, Jason Wang-Gillam, Andrea Research Article Patients with pancreatic cancer have dismal prognoses, and novel therapies are urgently needed. Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target. Direct targeting of the predominant KRAS pathways have been challenging and research into therapeutic strategies have been now refocused on pathways downstream of KRAS, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK [MEK]). We hypothesized that concurrent inhibition of the PI3K and MEK pathways would result in synergistic antitumor activity, as it would circumvent the compensatory feedback loop between the two pathways. We investigated the combined effect of the PI3K inhibitor, GDC0941, and the MEK inhibitor, AZD6244, on cell viability, apoptosis and cell signaling in a panel of pancreatic cancer cell lines. An in vivo analysis was conducted on pancreatic cancer xenografts. While BxPC-3 (KRAS wild type) and MIA PaCa-2 (KRAS mutated) cell lines were sensitive to GDC0941 and AZD6244 as single agents, synergistic inhibition of tumor cell growth and induction of apoptosis were observed in both cell lines when the two drugs were combined. Interestingly, phosphorylation of the cap-dependent translational components, 4E-binding protein (p-4E-BP1) and S6 was found to be closely associated with sensitivity to GDC0941 and AZD6244. In BxPC-3 cell xenografts, survival differences were observed between the control and the AZD6244, GDC0941, and combination groups. Our study provides the rationale for concurrent targeting of the PI3K and MEK pathways, regardless of KRAS status, and suggests that phosphorylation of 4E-BP1and S6 can serve as a predictive biomarker for response to treatment. Public Library of Science 2013-10-09 /pmc/articles/PMC3793961/ /pubmed/24130864 http://dx.doi.org/10.1371/journal.pone.0077243 Text en © 2013 Zhong et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Zhong, Hua Sanchez, Cesar Spitrzer, Dirk Plambeck-Suess, Stacy Gibbs, Jesse Hawkins, Williams G. Denardo, David Gao, Feng Pufahl, Robert A. Lockhart, Albert C. Xu, Mai Linehan, David Weber, Jason Wang-Gillam, Andrea
spellingShingle	Zhong, Hua Sanchez, Cesar Spitrzer, Dirk Plambeck-Suess, Stacy Gibbs, Jesse Hawkins, Williams G. Denardo, David Gao, Feng Pufahl, Robert A. Lockhart, Albert C. Xu, Mai Linehan, David Weber, Jason Wang-Gillam, Andrea Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models
author_facet	Zhong, Hua Sanchez, Cesar Spitrzer, Dirk Plambeck-Suess, Stacy Gibbs, Jesse Hawkins, Williams G. Denardo, David Gao, Feng Pufahl, Robert A. Lockhart, Albert C. Xu, Mai Linehan, David Weber, Jason Wang-Gillam, Andrea
author_sort	Zhong, Hua
title	Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models
title_short	Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models
title_full	Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models
title_fullStr	Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models
title_full_unstemmed	Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models
title_sort	synergistic effects of concurrent blockade of pi3k and mek pathways in pancreatic cancer preclinical models
description	Patients with pancreatic cancer have dismal prognoses, and novel therapies are urgently needed. Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target. Direct targeting of the predominant KRAS pathways have been challenging and research into therapeutic strategies have been now refocused on pathways downstream of KRAS, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK [MEK]). We hypothesized that concurrent inhibition of the PI3K and MEK pathways would result in synergistic antitumor activity, as it would circumvent the compensatory feedback loop between the two pathways. We investigated the combined effect of the PI3K inhibitor, GDC0941, and the MEK inhibitor, AZD6244, on cell viability, apoptosis and cell signaling in a panel of pancreatic cancer cell lines. An in vivo analysis was conducted on pancreatic cancer xenografts. While BxPC-3 (KRAS wild type) and MIA PaCa-2 (KRAS mutated) cell lines were sensitive to GDC0941 and AZD6244 as single agents, synergistic inhibition of tumor cell growth and induction of apoptosis were observed in both cell lines when the two drugs were combined. Interestingly, phosphorylation of the cap-dependent translational components, 4E-binding protein (p-4E-BP1) and S6 was found to be closely associated with sensitivity to GDC0941 and AZD6244. In BxPC-3 cell xenografts, survival differences were observed between the control and the AZD6244, GDC0941, and combination groups. Our study provides the rationale for concurrent targeting of the PI3K and MEK pathways, regardless of KRAS status, and suggests that phosphorylation of 4E-BP1and S6 can serve as a predictive biomarker for response to treatment.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793961/
_version_	1612017424952983552

Synergistic Effects of Concurrent Blockade of PI3K and MEK Pathways in Pancreatic Cancer Preclinical Models

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