Abstract
Abstract Pancreatic adenocarcinoma is a difficult cancer to treat with poor response rates to current therapies. Using a mouse model of pancreatic adenocarcinoma driven by endogenous expression of KRASG12D and p53R172H, we isolated heterogeneous tumor cell clones from a single tumor. Each of the cell clones has a unique genetic and protein expression signature, and they proliferate at different rates in vitro. Notably, only some of them are able to grow into colonies under anchorage-independent (AI) condition. We found that clones which can undergo AI growth have significantly higher phospho-ERK levels than the others, and the MEK inhibitors PD184352 and UO126 can suppress only some AI growth. We therefore looked for additional drivers of this cancer-associated AI growth and discovered that the canonical Wnt pathway, indicated by high transcription levels of Axin2 and Lgr5, is associated with AI growth in the pancreatic cancer cell clones that are less sensitive to the MEK inhibitors. In addition, two tankyrase inhibitors, XAV939 and IWR1, which stabilize Axin1 and enhance β-catenin degradation, inhibit AI growth in Wntactive cells, but not in ERK-dependent cells. Both tankyrase inhibitors downregulate Wnt-dependent Axin2 and Lgr5 transcription, without affecting phospho-ERK levels. Importantly, knockdown of β-catenin also impairs anchorage-independent growth only in Wnt-active cells. Thus, we have demonstrated for the first time that the canonical Wnt pathway is activated and contributes to AI growth in subclones of pancreatic cancer cells downstream of KRASG12D and p53R172H, and that Axin2 and Lgr5, but not all classical Wnt target genes (for example c-Myc), are involved. Hence, targeting Wnt in pancreatic cancer may be a viable option in treating KRAS- and p53-driven pancreatic cancer, but will probably need to be combined with multiple pathway inhibitors to deal with tumor heterogeneity. This abstract is also presented as Poster A46. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr PR13.
Published Version
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