Cotargeting MAPK and PI3K Signaling with Concurrent Radiotherapy as a Strategy for the Treatment of Pancreatic Cancer
- 1 May 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 11 (5), 1193-1202
- https://doi.org/10.1158/1535-7163.mct-12-0098
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. Mol Cancer Ther; 11(5); 1193–202. ©2012 AACR.Keywords
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This publication has 33 references indexed in Scilit:
- PKB/Akt promotes DSB repair in cancer cells through upregulating Mre11 expression following ionizing radiationOncogene, 2010
- PIK3CA Mutation Uncouples Tumor Growth and Cyclin D1 Regulation from MEK/ERK and Mutant KRAS SignalingCancer Research, 2010
- Mechanism of Radiosensitization by the Chk1/2 Inhibitor AZD7762 Involves Abrogation of the G2 Checkpoint and Inhibition of Homologous Recombinational DNA RepairCancer Research, 2010
- Inhibition of Hedgehog Signaling Enhances Delivery of Chemotherapy in a Mouse Model of Pancreatic CancerScience, 2009
- In vitro and In vivo Radiosensitization with AZD6244 (ARRY-142886), an Inhibitor of Mitogen-activated Protein Kinase/Extracellular Signal-regulated Kinase 1/2 KinaseClinical Cancer Research, 2009
- Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK InhibitionCancer Research, 2009
- Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancersNature Medicine, 2008
- Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancerJCI Insight, 2008
- BRAF mutation predicts sensitivity to MEK inhibitionNature, 2005
- Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genesCell, 1988