Abstract PO002: Inducing homologous recombination deficiency in uterine serous cancer (USC) using AVB-500, a receptor tyrosine kinase AXL inhibitor

Abstract

Abstract Background: Evidence suggests that inducing homologous recombination deficiency (HRD) can be a therapeutic target in endometrial cancer (EC). Given this, we determined whether AVB-500, an AXL inhibitor, could induce HRD measured by a reduction of RAD51 foci in response to DNA damage in a uterine serous cancer (USC). Methods: Baseline homologous recombination (HR) status was determined after inducing DNA damage by radiating USC cell lines (ARK1 and ARK4) with 10Gy radiation treatment (RT) and identifying RAD51 foci by immunofluorescence (IF). Both radiated and non-radiated cells were quantified in both cell lines. Cell lines were considered to be HR proficient if over 30% of the cells expressed RAD51 (>5 foci per cell). AVB-500 (Aravive Biologics, Houston, TX) was given prior to radiation after baseline HR status was established. IF was conducted using a Leica confocal microscope and foci were quantified using FociCounter. Results: Both ARK1 and ARK4, showed HR proficiency at baseline. After radiation, there was an increase in gamma-H2Ax indicative of DNA damage and an appropriate increase in RAD51 foci in response. However, when cells were treated with AVB-500 prior to radiation, there was a decrease in RAD51 foci when compared to radiation alone in both ARK1 (2.7 foci for AVB + RT vs 7.3 foci for RT only, p=0.0003) and ARK4 (6.3 foci for AVB + RT vs 13.0 foci for RT only, p=0.0054). Furthermore, after treatment with AVB-500 followed by RT, the proportion of ARK1 cells expressing RAD51 decreased to 21%, indicating HR deficiency. Conclusions: ARK1 and ARK4 are HR proficient at baseline. Pretreatment with AVB500 followed by RT led to a decrease in RAD51 foci suggestive of inducing HRD. Additional therapeutic and mechanistic experiments are ongoing. Citation Format: Michael D. Toboni, Barbara Blachut, Elena Lomonosova, Dineo Khabele, Lindsay Kuroki, Andrea Hagemann, Carolyn McCourt, Premal Thaker, David Mutch, Matthew Powell, Katherine Fuh. Inducing homologous recombination deficiency in uterine serous cancer (USC) using AVB-500, a receptor tyrosine kinase AXL inhibitor [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO002.