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PLoS One. 2012;7(12):e49707. doi: 10.1371/journal.pone.0049707. Epub 2012 Dec 3.

Metastatic pancreatic cancer is dependent on oncogenic Kras in mice.

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1
Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, United States of America.

Abstract

Pancreatic cancer is one of the deadliest human malignancies, and its prognosis has not improved over the past 40 years. Mouse models that spontaneously develop pancreatic adenocarcinoma and mimic the progression of the human disease are emerging as a new tool to investigate the basic biology of this disease and identify potential therapeutic targets. Here, we describe a new model of metastatic pancreatic adenocarcinoma based on pancreas-specific, inducible and reversible expression of an oncogenic form of Kras, together with pancreas-specific expression of a mutant form of the tumor suppressor p53. Using high-resolution magnetic resonance imaging to follow individual animals in longitudinal studies, we show that both primary and metastatic lesions depend on continuous Kras activity for their maintenance. However, re-activation of Kras* following prolonged inactivation leads to rapid tumor relapse, raising the concern that Kras*-resistance might eventually be acquired. Thus, our data identifies Kras* as a key oncogene in pancreatic cancer maintenance, but raises the possibility of acquired resistance should Kras inhibitors become available for use in pancreatic cancer.

PMID:
23226501
PMCID:
PMC3513322
DOI:
10.1371/journal.pone.0049707
[Indexed for MEDLINE]
Free PMC Article
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