Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer.
The activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR in...
Main Authors: | , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2014-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC4234626?pdf=render |
id |
doaj-b1c9a4e1dffc414aa91616e478557aca |
---|---|
record_format |
Article |
spelling |
doaj-b1c9a4e1dffc414aa91616e478557aca2020-11-24T20:50:08ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-01911e11303710.1371/journal.pone.0113037Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer.Todd M PittsTimothy P NewtonErica L Bradshaw-PierceRebecca AddisonJohn J ArcaroliPeter J KlauckStacey M BagbyStephanie L HyattAlicia PurkeyJohn J TentlerAik Choon TanWells A MessersmithS Gail EckhardtStephen LeongThe activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX).The anti-proliferative effects of PF-502 and PD-901 were assessed as single agents and in combination against a panel of CRC cell lines with various molecular backgrounds. Synergy was evaluated using the Bliss Additivity method. In selected cell lines, we investigated the combination effects on downstream effectors by immunoblotting. The combination was then evaluated in several fully genetically annotated CRC PDTX models.The in vitro experiments demonstrated a wide range of IC50 values for both agents against a cell line panel. The combination of PF-502 and PD-901 demonstrated synergistic anti-proliferative activity with Bliss values in the additive range. As expected, p-AKT and p-ERK were downregulated by PF-502 and PD-901, respectively. In PDTX models, following a 30-day exposure to PF-502, PD-901 or the combination, the combination demonstrated enhanced reduction in tumor growth as compared to either single agent regardless of KRAS or PI3K mutational status.The combination of a PI3K/mTOR and a MEK inhibitor demonstrated enhanced anti-proliferative effects against CRC cell lines and PDTX models.http://europepmc.org/articles/PMC4234626?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Todd M Pitts Timothy P Newton Erica L Bradshaw-Pierce Rebecca Addison John J Arcaroli Peter J Klauck Stacey M Bagby Stephanie L Hyatt Alicia Purkey John J Tentler Aik Choon Tan Wells A Messersmith S Gail Eckhardt Stephen Leong |
spellingShingle |
Todd M Pitts Timothy P Newton Erica L Bradshaw-Pierce Rebecca Addison John J Arcaroli Peter J Klauck Stacey M Bagby Stephanie L Hyatt Alicia Purkey John J Tentler Aik Choon Tan Wells A Messersmith S Gail Eckhardt Stephen Leong Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer. PLoS ONE |
author_facet |
Todd M Pitts Timothy P Newton Erica L Bradshaw-Pierce Rebecca Addison John J Arcaroli Peter J Klauck Stacey M Bagby Stephanie L Hyatt Alicia Purkey John J Tentler Aik Choon Tan Wells A Messersmith S Gail Eckhardt Stephen Leong |
author_sort |
Todd M Pitts |
title |
Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer. |
title_short |
Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer. |
title_full |
Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer. |
title_fullStr |
Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer. |
title_full_unstemmed |
Dual pharmacological targeting of the MAP kinase and PI3K/mTOR pathway in preclinical models of colorectal cancer. |
title_sort |
dual pharmacological targeting of the map kinase and pi3k/mtor pathway in preclinical models of colorectal cancer. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2014-01-01 |
description |
The activation of the MAPK and PI3K/AKT/mTOR pathways is implicated in the majority of cancers. Activating mutations in both of these pathways has been described in colorectal cancer (CRC), thus indicating their potential as therapeutic targets. This study evaluated the combination of a PI3K/mTOR inhibitor (PF-04691502/PF-502) in combination with a MEK inhibitor (PD-0325901/PD-901) in CRC cell lines and patient-derived CRC tumor xenograft models (PDTX).The anti-proliferative effects of PF-502 and PD-901 were assessed as single agents and in combination against a panel of CRC cell lines with various molecular backgrounds. Synergy was evaluated using the Bliss Additivity method. In selected cell lines, we investigated the combination effects on downstream effectors by immunoblotting. The combination was then evaluated in several fully genetically annotated CRC PDTX models.The in vitro experiments demonstrated a wide range of IC50 values for both agents against a cell line panel. The combination of PF-502 and PD-901 demonstrated synergistic anti-proliferative activity with Bliss values in the additive range. As expected, p-AKT and p-ERK were downregulated by PF-502 and PD-901, respectively. In PDTX models, following a 30-day exposure to PF-502, PD-901 or the combination, the combination demonstrated enhanced reduction in tumor growth as compared to either single agent regardless of KRAS or PI3K mutational status.The combination of a PI3K/mTOR and a MEK inhibitor demonstrated enhanced anti-proliferative effects against CRC cell lines and PDTX models. |
url |
http://europepmc.org/articles/PMC4234626?pdf=render |
work_keys_str_mv |
AT toddmpitts dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT timothypnewton dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT ericalbradshawpierce dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT rebeccaaddison dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT johnjarcaroli dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT peterjklauck dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT staceymbagby dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT stephanielhyatt dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT aliciapurkey dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT johnjtentler dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT aikchoontan dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT wellsamessersmith dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT sgaileckhardt dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer AT stephenleong dualpharmacologicaltargetingofthemapkinaseandpi3kmtorpathwayinpreclinicalmodelsofcolorectalcancer |
_version_ |
1716804544117080064 |