Abstract 4569: APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC)
Authors: Zhou Yu, Eric Liang, Daojie Liu, Bingxing Wu, Xinyi Yao, Yanqiu Ji, Dajun Yang, Yifan Zhai
Journal: Cancer Research (2024)

Abstract Ovarian cancer is the leading cause of cancer-related death in women and most cases are diagnosed at later stages, with distant metastasis. Standard-of-care therapy is surgery followed by platinum and paclitaxel; however, most patients who initially respond to therapy eventually relapse after developing metastatic disease and chemoresistance. FAK overexpression or activation occurs in a substantial proportion of EOCs and is predictive of poor clinical outcomes. Recent studies have reported that FAK plays an important role in cell migration and chemoresistance, rendering FAK inhibition a promising treatment approach to reduce metastasis of tumor cells and sensitize them to chemotherapy. The aim of this study was to evaluate the antitumor efficacy of investigational APG-2449, a novel FAK inhibitor, combined with PLD, a commonly used chemotherapy, in relapsed or refractory ovarian cancer. Four EOC cell lines (OVCAR-3, SK-OV-3, A2780, and Kuramochi) were used for in vitro experiments. Cell proliferation was measured by CellTiter-Glo assays. Cell migration ability was assessed by wound healing assays. OVCAR-3 xenograft and luciferase-tagged ID8 (ID8-Luc) peritoneal syngeneic models were established to evaluate the synergistic antitumor efficacy of combined APG-2449 and PLD in vivo. APG-2449 combined with doxorubicin showed synergistic antiproliferative effects in both platinum-resistant (OVCAR-3 and SK-OV-3) and platinum-sensitive (A2780 and Kuramochi) cell lines. In wound healing assays, FAK inhibition via APG-2449 alone attenuated migration of ovarian cancer cells (SK-OV-3, OVCAR-3, and ID8-Luc) in a dose-dependent manner. In the OVCAR-3 xenograft model, combined APG-2449 and PLD demonstrated enhanced antitumor effects compared with either APG-2449 or PLD monotherapy (synergistic index, 1.33). In the ID8-Luc peritoneal syngeneic model, the combination regimen outperformed PLD or APG-2449 monotherapy in tumor growth inhibition. This inhibitory effect persisted more than 1 month after stopping combination treatment, whereas the monotherapy groups experienced rapid disease relapse. The combination group also exhibited the longest ascites-free and survival times compared with PLD or APG-2449 monotherapy groups. Overall, our data suggest that inhibition of FAK by APG-2449 enhances the antitumor effect of PLD in EOC cell lines and the OVCAR-3 xenograft mouse model. The combination regimen can also prolong ascites-free and survival times, as shown in the ID8-Luc peritoneal syngeneic model. These promising results support future clinical development of this combination treatment for ovarian cancer. Citation Format: Zhou Yu, Eric Liang, Daojie Liu, Bingxing Wu, Xinyi Yao, Yanqiu Ji, Dajun Yang, Yifan Zhai. APG-2449, a novel focal adhesion kinase (FAK) inhibitor, inhibits metastasis and enhances the antitumor efficacy of PEGylated liposome doxorubicin (PLD) in epithelial ovarian cancer (EOC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4569.