Abstract 3922: A p53-deficient, PTK2/cMyc-driven ovarian cancer mouse model for preclinical drug discovery

Abstract Background: Ovarian cancer (OC) remains a significant health issue for women due to its late diagnosis and chemoresistance. Currently, there is no relevant mouse OC model for preclinical drug screening and treatment. Methods: We established a mouse OC cell line model, PC53K, by transforming primary ovarian surface epithelial cells through CRISPR/Cas9-mediated TP53 knockout and simultaneous overexpression of human PTK2 and cMyc. We further developed the paclitaxel-resistant PC53K/TxR cell line. PC53K and PC53K/TxR cell lines were validated in vitro and in vivo in an orthotopic mouse model. We also evaluated the efficacy of two novel tubulin inhibitors, the clinical drug VERU-111 and the preclinical compound SB-216, using the PC53K/TxR model in vitro and in vivo. Results: Mice intrabursally injected with PC53K cells exhibited bloody ascites, aggressive primary tumor growth and widespread metastasis, which faithfully recapitulates the phenotypes of human ovarian serous adenocarcinoma. Additionally, the paclitaxel-resistant PC53K/TxR cell line shows significant higher IC50 for paclitaxel than PC53K cell line, indicating it is a valuable tool for studying OC chemoresistance. Compounds VERU-111 and SB-216 significantly inhibited tumor growth and metastasis in orthotopic OC mouse models by overcoming chemoresistance. This study demonstrates the effectiveness of the PC53K and PC53K/TxR models for preclinical drug screening and validates the potential of VERU-111 and SB-216 in overcoming chemoresistance and treating OC. Significance: The development of the PC53K and PC53K/TxR mouse models represents a significant advancement in OC research. By mimicking the genetic profile, aggressive behavior and chemoresistance of human OC, these models provide a robust platform for preclinical drug discovery and development. Citation Format: Ziping Liu, Wenjing Zhang, Xinxin Zhao, Yongshuai Li, Xiaoya Hou, Satyanarayana Pochampally, Shelby Waddell, Shiji Song, Yaohong Wang, Lawrence M. Pfeffer, Duane D. Miller, Junming Yue, Wei Li. A p53-deficient, PTK2/cMyc-driven ovarian cancer mouse model for preclinical drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3922.