Abstract:
:There is an urgent need for the development of novel therapies to treat pancreatic cancer, which is among the most lethal of all cancers. KRAS-activating mutations, which are found in more than 90% of pancreatic adenocarcinomas, drive tumor dependency on the Ras/MAPK and Akt signaling pathways. Radiation is currently being explored as a component of the standard treatment regimen for pancreatic cancer. This study's purpose was to test the hypothesis that MAP kinase kinase (MEK or MAP2K) inhibitors will offer clear therapeutic benefit when integrated into radiotherapy treatment regimens for treatment of this disease. We explored the activation of the mitogen-activated protein kinase (MAPK) and Akt pathways in response to radiation in multiple pancreatic tumor cell lines. Small molecule inhibitors of MEK (PD0325901) and Akt (API-2) were subsequently evaluated for their radiosensitizing potential alone and in combination. In vivo efficacy was tested in subcutaneous MIA-PaCa2 xenografts. Phosphorylated levels of extracellular signal-regulated kinase (ERK)-1/2 and Akt were found to increase in response to radiation treatment in our pancreatic tumor cell line panel. MEK inhibitor-induced radiosensitization was observed in vitro and in vivo. The further addition of an Akt inhibitor to the MEK inhibitor/radiation regimen resulted in enhanced therapeutic gain as determined by increased radiosensitization and tumor cell death. In conclusion, MEK inhibition results in growth arrest, apoptosis, and radiosensitization of multiple preclinical pancreatic tumor models, and the effects can be enhanced by combination with an Akt inhibitor. These results provide rationale for further testing of a treatment regimen in pancreatic cancer that combines MEK inhibition with radiation, optimally in conjunction with Akt inhibition.
journal_name
Mol Cancer Therjournal_title
Molecular cancer therapeuticsauthors
Williams TM,Flecha AR,Keller P,Ram A,Karnak D,Galbán S,Galbán CJ,Ross BD,Lawrence TS,Rehemtulla A,Sebolt-Leopold Jdoi
10.1158/1535-7163.MCT-12-0098subject
Has Abstractpub_date
2012-05-01 00:00:00pages
1193-202issue
5eissn
1535-7163issn
1538-8514pii
1535-7163.MCT-12-0098journal_volume
11pub_type
杂志文章abstract::The functional and therapeutic importance of the Warburg effect is increasingly recognized, and glycolysis has become a target of anticancer strategies. We recently reported the identification of a group of novel small compounds that inhibit basal glucose transport and reduce cancer cell growth by a glucose deprivatio...
journal_title:Molecular cancer therapeutics
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