Abstract B66: MAPK signaling mediates Kras-driven PanIN formation and maintenance.

Pancreatic ductal adenocarcinoma (PDA) is almost uniformly associated to the presence of a constitutive active mutation of the Kras gene, most often K-rasG12D (hereby Kras*). Several studies using mouse models have shown that mutant Kras* drives the formation of pancreatic intraepithelial neoplasia (PanIN), the most common precursor lesions for pancreatic cancer. Moreover, our group has recently shown that Kras* is required for maintenance of PanINs and of invasive PDA. However, the lack of inhibitors targeting Kras prevents clinical applications of our findings. Therefore, we have set out to explore which downstream effector(s) of Kras mediate its effects during pancreatic carcinogenesis, with the goal to identify potential therapeutic targets. The MAPK/ERK pathway is activated by Kras, and its activation accompanies PanIN formation and is retained in invasive tumors. Inhibitors for the key pathway component MEK are currently in clinical trials for several malignancies. Here, we have explored the effect of inhibiting the MAPK/ERK pathway during pancreatic carcinogenesis. We have utilized two mouse models of pancreatic cancer, the KC mouse, based on tissue-specific expression of Kras*, and the iKras* mouse that allows inducible, and reversible, expression of Kras* in the pancreas. In a first set of experiments, we investigated the role of MAPK/ERK signaling during early tumorigenesis. Inhibition of MAPK/ERK signaling in vivo, prevents as well as PanIN formation in both iKras* and KC mice. To monitor individual acini over time to address whether MAPK/ERK signaling is required for acinar-ductal metaplasia (ADM), believed to precede PanINs, we utilized a 3-D culture system. Acini from both KC and iKras* models exhibit ADM over a period of three to five days in culture. Blocking the MAPK/ERK pathway inhibited ADM, thus confirming our in vivo results. In a second set of experiments, we set out to study the role of MAPK signaling in the maintenance of PanIN lesions. Treatment of PanIN-bearing iKras* mice with a MEK inhibitor resulted in regression of the PanIN lesions and regeneration of acinar tissue. In addition, we observed reversion of the fibrosis and inflammatory response that accompanies PanIN lesions, recapitulating the effect of Kras* inactivation. Taken together, our data indicate that activation of the MAPK/ERK pathway during tumorigenesis is required for both the formation and maintenance PanIN lesions. Our future directions include long-term inhibition of MAPK/ERK signaling in PanINs. Moreover, we will investigate the effect of pathway inhibition on invasive tumors, both in spontaneous and transplantation models. Finally, we will study the effect of MAPK/ERK inhibition in primary human pancreatic cancer cells. Citation Format: Meredith A. Collins, Yaqing Zhang, Sabita Rakshit, Judith S. Sebolt-Leopold, Marina Pasca di Magliano. MAPK signaling mediates Kras-driven PanIN formation and maintenance. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B66.