Co-Targeting MAPK and PI3K Signaling with Concurrent Radiotherapy as a Strategy for the Treatment of Pancreatic Cancer

• Published in: Molecular cancer therapeutics Vol. 11; no. 5; pp. 1193 - 1202
• Main Authors: Williams, Terence M., Flecha, Athena R., Keller, Paul, Ram, Ashwin, Karnak, David, Galbán, Stefanie, Galbán, Craig J., Ross, Brian D., Lawrence, Theodore S., Rehemtulla, Alnawaz, Sebolt-Leopold, Judith
• Format: Journal Article
• Language: English
• Published: 12-03-2012
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-12-0098

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 >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 MEK inhibitors will offer clear therapeutic benefit when integrated into radiotherapy treatment regimens for treatment of this disease. We explored the activation of the 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 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.