Abstract 5090: Targeted inhibition of MEK and AKT pathways in combination with radiation as a novel treatment paradigm in pancreatic cancer

Abstract

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 >90% of pancreatic adenocarcinomas, drive tumor dependency on the RAS/MAPK and AKT signaling pathways. Radiation is currently being explored in both the post-operative and inoperable settings as a component of the standard treatment regimen for pancreatic cancer. The purpose of this study 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 MiaPaCa2 xenografts and diffusion MRI (dMRI) was explored as a surrogate biomarker of response. Phosphorylated levels of ERK 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 as well as in vivo, where changes in dMRI strongly correlated with changes in tumor burden. The further addition of an AKT inhibitor to the MEK inhibitor/radiation regimen resulted in enhanced therapeutic gain as measured by 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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5090. doi:10.1158/1538-7445.AM2011-5090