Abstract 1679: APG-2449, a novel focal adhesion kinase (FAK) inhibitor, enhances the antitumor activity of chemotherapy in preclinical models of small-cell lung cancer (SCLC) with activated FAK

Abstract Background: SCLC is a genetically heterogeneous disease with no standardized targeted therapy options. Despite the recent advancement of immune checkpoint inhibitors, improvements in overall survival have been modest, and platinum-based chemotherapy combined with topoisomerase inhibitors remains the standard of care in SCLC. FAK, a non-receptor tyrosine kinase, has been reported to regulate cellular proliferation, migration, invasion, and DNA-damage repair. Previous studies have shown that FAK is amplified and overexpressed in SCLC tumors. Although non-small-cell lung cancer cells harboring FAK6, 7 (splicing isoforms of FAK that increase phosphorylation of FAK [pFAK]) are more sensitive to FAK inhibition than wild-type FAK (FAKWT), the expression and implications of FAK6, 7 expression in SCLC remain unclear. Given the role of FAK in cancer progression, we hypothesized that inhibition of FAK would augment the antitumor effects of chemotherapy in SCLC. The aim of this study was to evaluate the antitumor activity of investigational agent APG-2449 alone and combined with chemotherapy in SCLC. Methods: Cellular proliferation was measured by CellTiter-Glo® assays and apoptosis assessed via flow cytometry. Protein expression levels were examined via western blot. An H446 xenograft model was used to evaluate antitumor effects in vivo. Results: SCLC cell lines harboring FAK6, 7 (H446, H69, and H526) showed increased sensitivity to APG-2449 in a dose-dependent manner compared to a FAKWT cell line (DMS-114). When combined with chemotherapy (topotecan or etoposide plus carboplatin), APG-2449 synergistically decreased cell viability and increased apoptosis in H446 and H526 cell lines. Mechanistically, APG-2449 combined with topotecan and etoposide plus carboplatin enhanced DNA damage and apoptosis compared to either therapy alone in western blot assays. APG-2449 synergistically enhanced the antitumor effects of topotecan (synergy ratio: 22.08) and etoposide plus carboplatin (synergy ratio: 3.81) in the H446 xenograft model. Conclusions: Novel FAK inhibitor APG-2449 demonstrated a synergistic enhancement when combined with first- and second-line chemotherapies in SCLC, significantly increasing antitumor activity. These encouraging findings support further clinical development of APG-2449 for the treatment of patients with SCLC. Citation Format: Zhou Yu, Zhiyan Liang, Xinyi Yao, Daojie Liu, Dajun Yang, Yifan Zhai. APG-2449, a novel focal adhesion kinase (FAK) inhibitor, enhances the antitumor activity of chemotherapy in preclinical models of small-cell lung cancer (SCLC) with activated FAK [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 1679.