Abstract A07: Mst1r inhibition with LY2801653 increases survival in mice bearing aggressive pancreatic adenocarcinoma organoid model
Authors: Childers Betzaira G. , Sood Divya , Jaquish Dawn , Lowy Andrew M. 
Published: March 2020

Background: RON/MST1R is a receptor tyrosine kinase variably expressed in epithelial cells and macrophages and overexpressed in epithelial cancers. It is involved in downstream signaling pathways that regulate cell survival, proliferation, and invasion. In efforts to understand the role of Mst1r in pancreatic cancer progression, genetically engineered mice were created with Mst1r loss of function or Mst1r overexpression. Those with Mst1r overexpression demonstrated earlier metastasis and overall decreased survival. Mst1r and several other kinases are the primary targets of LY2801653, a small-molecule inhibitor. Given the findings in genetically engineered models, we sought to evaluate the effects of Mst1r inhibition with LY2801653 in an immune-competent mouse bearing an aggressive orthotopic, organoid-derived pancreatic cancer.

Methods: All animal procedures were conducted with approval of the Institutional Animal Care and Use Committee at UCSD. Pancreatic adenocarcinoma organoid cell line KPC484 was derived from spontaneous growth in KRAS/p53 mice of B6.129S background. F1 hybrid male and female mice underwent orthotopic injection of the above-mentioned organoid line at 6-8 weeks of life. Daily dosing with Mst1r inhibitor LY2801653 was initiated one week after surgery for a total treatment time of two weeks or until meeting death criteria when evaluating for survival. Control groups received 10% Acacia Gum via oral gavage for the same duration. Mice were euthanized and the primary tumor was collected for weight, flow cytometric markers, histology, and immunohistochemistry.

Results: Mst1r inhibition with LY2801653 in F1 hybrid mice resulted in a significant reduction in primary tumor weight when compared to control groups (p-value = 0.007). Flow cytometry demonstrated significant differences in macrophage cell populations within the tumor microenvironment. Along a phenotypic continuum, macrophages may promote acute inflammation (M1), tissue rebuilding (M2), or some combination thereof. Mst1r inhibition in male mice led to a significant increase in the M1 macrophage phenotype and a significant decrease in the M2 macrophage phenotype with p-values of (0.004) and (0.008) respectively. Survival data were acquired from two separate experiments totaling thirty vehicle mice and thirty-two treatment mice. A significant survival benefit was observed in the treatment group (p-value = 0.01).

Conclusion: An urgent need persists to uncover alternative therapeutic options for pancreatic adenocarcinoma. Here, we utilize an aggressive KPC organoid model to test the in vivo effects of kinase inhibitor LY2801653. Data in our lab demonstrate a modulation of the macrophage phenotype toward M1, a significant reduction in primary tumor size, and a significant survival benefit with treatment. These findings urge the consideration of this drug as a candidate for combination therapy in pancreatic adenocarcinoma.

Citation Format: Betzaira G. Childers, Divya Sood, Dawn Jaquish, Andrew M. Lowy. Mst1r inhibition with LY2801653 increases survival in mice bearing aggressive pancreatic adenocarcinoma organoid model [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A07.