Abstract AS19: The role of the receptor tyrosine kinase AXL in an immunocompetent mouse model of invasive endometrioid ovarian cancer

Abstract

Abstract Objective: To evaluate the role of AXL in an immunocompetent model of ovarian cancer metastasis. Methods: Immunohistochemical staining of ovarian cancer tissue microarrays of advanced stage, high-grade epithelial ovarian cancer specimens for AXL expression was performed and correlated with overall survival. Metastatic endometrioid ovarian cancer was generated through intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl mouse model. LSL-K-rasG12D/+Ptenfl/fl Axl+/+ and LSL-K-rasG12D/+Ptenfl/flAxl−/−were used to evaluate the role of AXL. Necropsy was performed to evaluate burden of the primary and metastatic tumors. Hematoxylin and eosin (H&E) staining was used to confirm tumor formation or lack of tumor. Western blotting was performed to evaluate protein expression. Results: Of the 80 patient-derived primary ovarian tumor specimens, 76% (61) of advanced stage, high-grade epithelial ovarian cancer specimens had 3+ transmembrane AXL staining whereas 24% (19) of advanced stage, high-grade epithelial ovarian cancer specimens had no AXL staining. When correlated with overall survival, patients with tumors that had no AXL expression had a median survival of 53 months vs. 45 months for those with 3+AXL expression (p=0.12). The majority of intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl Axl+/+ mice had primary (78%) and metastatic tumor formation (86%) whereas the majority of LSL-K-rasG12D/+Ptenfl/flAxl−/− had primary tumor formation (64%) but few had metastatic tumors (28%) (p<0.05). There was no difference in primary tumor weight between the two groups: 120mg for Axl+/+ vs. 110mg for Axl−/−. Metastatic tumors were microscopic and therefore unable to be resected and weighed prior to identification by H&E staining. Western blotting of primary and metastatic tumors from LSL-KrasG12D/+Ptenfl/fl Axl+/+ showed high AXL expression compared to no AXL expression in the ovaries of normal mice. Conclusions: AXL expression in advanced stage epithelial ovarian cancer correlated with lower overall survival. Primary ovarian and metastatic tumors in this intrabursal AdCre-infected LSL-K-rasG12D/+Ptenfl/fl mouse model express AXL. Deletion of the receptor tyrosine kinase, AXL, in this conditional genetically engineered mouse model of endometrioid ovarian cancer resulted in inhibition of metastatic tumor formation. AXL is a critical factor driving metastasis in this immunocompetent murine model of metastatic ovarian cancer. Citation Format: Katherine Fuh, Erinn Rankin, Colleen Wu, Anh Diep, Amato J. Giaccia. The role of the receptor tyrosine kinase AXL in an immunocompetent mouse model of invasive endometrioid ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS19.