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Modeling targeted inhibition of MEK and PI3 kinase in human pancreatic cancer

Junttila, MR and Devasthali, V and Cheng, JH and Castillo, J and Metcalfe, C and Clermont, AC and Den, OD and Chan, E and Bou-Reslan, H and Cao, T and Forrest, W and Nannini, MA and French, DM and Carano, R and Merchant, M and Hoeflich, KP and Singh, M (2014) Modeling targeted inhibition of MEK and PI3 kinase in human pancreatic cancer. Mol Cancer Ther .

Abstract

Activating mutations in the KRAS oncogene occur in approximately 90% of pancreatic cancers, resulting in aberrant activation of the mitogen activated kinase (MAPK) and the phospho-inositol 3 kinase (PI3K) pathways, driving malignant progression. Significant efforts to develop targeted inhibitors of nodes within these pathways are underway and several are currently in clinical trials for patients with KRAS mutant tumors, including pancreatic cancer patients. To model MEK and PI3K inhibition in late-stage pancreatic cancer, we conducted preclinical trials with a mutant Kras-driven genetically engineered mouse model (GEMM) that faithfully recapitulates human pancreatic ductal adenocarcinoma development. Treatment of advanced disease with either a MEK (GDC-0973) or PI3K inhibitor (GDC-0941) alone showed modest tumor growth inhibition and did not significantly enhance overall survival. However, combination of the two agents resulted in a significant survival advantage as compared to control tumor-bearing mice. To model the clinical scenario, we also evaluated the combination of these targeted agents with gemcitabine, the current standard of care chemotherapy for pancreatic cancer. The addition of MEK or PI3K inhibition to gemcitabine, or the triple combination regimen incrementally enhanced overall survival as compared to gemcitabine alone. These results are reminiscent of the survival advantage conferred in this model and in patients by the combination of gemcitabine and erlotinib, an approved therapeutic regimen for advanced non-resectable pancreatic cancer. Taken together, these data indicate that inhibition of MEK and PI3K alone or in combination with chemotherapy do not confer a dramatic improvement as compared to currently available therapies for pancreatic cancer patients

Item Type: Article
Additional Information: NIBR author: Singh, M institute: NIBR contributor address: Molecular Biology, Genentech, Inc. junttila.melissa@gene.comMolecular Biology, Genentech, IncMolecular Biology, Genentech, IncES Biomarker Development, Genentech, IncMolecular Biology, Genentech IncResearch, Genentech, IncTranslational Oncology, Genentech, IncCancer Signaling and Translational Oncology, GenentechTumor Biology and Angiogenesis, Genentech, IncBiomedical Imaging, Genentech, IncBiostatistics, Genentech. IncTranslational Oncology, Genentech, IncPathology, Gilead SciencesBiomedical Imaging Dept., Genentech, IncCancer Signaling and Translational Oncology, Genentech, IncTranslational Oncology, GenentechNovartis Institutes for Biomedical Research
Date Deposited: 13 Oct 2015 13:11
Last Modified: 13 Oct 2015 13:11
URI: https://oak.novartis.com/id/eprint/24938

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