Abstract 3231: Inhibition of focal adhesion kinase enhances antitumor response of immune checkpoint inhibitor therapy in laryngeal cancer

Introduction: Laryngeal squamous cell carcinoma (LSCC), a subtype of head and neck squamous cell carcinoma (HNSCC), is projected to account for 12,650 new cases and 3,880 deaths in the United States in 2024. Key risk factors include smoking, alcohol abuse, and exposure to carcinogens like agent orange and asbestos. Active-duty service members and veterans face a heightened risk of developing LSCC. Curative standard treatment involves surgery, radiation, and platinum-based chemoradiation for laryngeal preservation. However, 25-50% of patients develop recurrence, often requiring salvage laryngectomy, which severely impacts their quality of life. We investigated the efficacy of Focal adhesion kinase inhibitors (FAKi), alone and in combination with immune checkpoint inhibitors (ICI), as potential therapeutic options for platinum-resistant LSCC. Methods: We conducted an IRB-approved retrospective pilot study of 12 formalin-fixed paraffin-embedded (FFPE) LSCC tumor samples from smokers treated at the City of Hope. RNA was extracted from tumors and normal tissues and analyzed by NanoString Cancer and Immune Profiling Panels. FAKi screening was conducted using the CCK-8 cell viability assay. RNA-seq was performed to assess global changes in gene expression profiles. Syngeneic mouse models using MOC2 cell lines were utilized to evaluate the therapeutic efficacy of the FAKi in combination with ICI. Results: Comparative analysis between normal and tumor tissues of 12 FFPE LSCC revealed upregulation of genes associated with cell-to-cell and cell-to-matrix adhesion, contributing to PI3K/AKT signaling. Tumor tissues also showed increased expression of genes involved in cell cycle regulation and DNA repair. Immune profiling of the same LSCC samples revealed CD4+ regulatory cells as the primary tumor infiltrating lymphocytes, underscoring the predominant immunosuppressive environment of LSCC. To investigate the significance of adhesion-dependent signaling, we used two human laryngeal cancer cell lines resistant to cisplatin: SCC17a and SQ20B. Among ten FAKi, TAE226 showed the most powerful inhibitory effect on cell growth in both cell lines. RNA-seq analysis revealed that TAE226 inhibits FAK phosphorylation, leading to the inhibition of genes that contribute to PI3K signaling. Additionally, it suppresses the expression of genes involved in the cell cycle and DNA repair. In the syngeneic mouse model, TAE226 showed a powerful synergistic effect with the ICI on the suppression of tumor growth, significantly prolonging the survival of the mice compared to ICI or the FAKi monotherapy groups. Conclusion: Our study is the first to show synergism of FAKi and ICI in platinum-resistant LSCC in vitro and in a syngeneic HPV-negative HNSCC mouse model in vivo. This represents an important rationale for the translation of this therapeutic combination in platinum-resistant LSCC. Citation Format: Atish Ranjan Mohanty, Dana Do, Sharad Singhal, Haiqing Li, Sravani Ramisetty, Raju Pillai, Sultatna Shoukath, Prakash Kulkarni, Michelle Afkhami, Sue Chang, Ellie Maghami, Ravi Salgia, Erminia Massarelli. Inhibition of focal adhesion kinase enhances antitumor response of immune checkpoint inhibitor therapy in laryngeal cancer [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 3231.