Abstract 4690: Radio-sensitizing activity in apoptosis pathway in HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC)

Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide, presenting as two distinct diseases: HPV-positive HNSCC driven by high-risk human papillomavirus (HPV) infections; and HPV-negative HNSCC associated with heavy tobacco and alcohol use. Poor prognosis in HNSCC is partly attributed to therapy resistance, which differs between the two subtypes and is influenced by their underlying mechanism. Accumulating evidence points to dysregulation of the apoptotic pathway in HNSCC tumors via overexpression of Inhibitor of Apoptosis Proteins (IAPs). This results in evasion of cell death and makes these proteins critical therapeutic targets. Second mitochondria-derived activator of caspases (SMAC) mimetics, or IAP antagonists, are being explored as anti-cancer agents, especially in combination with radiation therapy. This study evaluates the efficacy of the IAP inhibitor AT406, alone and with radiation, in both HPV positive (UM-SCC47 and UD-SCC2) and HPV-negative (Cal27 and DET562) HNSCC cell lines. Preliminary findings suggest AT406 reduces cell viability in both subtypes, with HPV-positive cells exhibiting greater sensitivity, particularly in combination with radiation. On the other hand, HPV-negative cells show less pronounced reductions in cell viability, suggesting subtype-specific resistance mechanism. This trend underscores the potential of AT406 as a radio-sensitizing agent and highlight differences in therapeutic response between HPV-positive and HPV-negative HNSCC. Ongoing studies aim to confirm these findings and elucidate the molecular mechanism driving these differential responses. Apoptotic activity will be assessed through Caspase-3/7 activity, and expression of IAP proteins (cIAP1, cIAP2 and XIAP) will be evaluated using western blotting. In addition, Liquid Chromatography- Mass Spectrometry (LC-MS/MS) is being utilized to profile changes in protein expression under different treatment conditions to identify molecular contributors to resistance mechanisms. These studies aim to provide mechanistic insights into IAP inhibition and inform the development of combination therapies outcomes in HNSCC. Citation Format: Loren D. Lopez Rivera, Elizabeth Boeree, Kwang P. Nickel, Zafer Gurel, Randall J. Kimple. Radio-sensitizing activity in apoptosis pathway in HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) [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 4690.