Journal Article

Molecular imaging predicts trastuzumab‐deruxtecan (T‐DXd) response in head and neck cancer xenograft models

Kondo, Takahito, McAdoo, Ashtyn, Rosenthal, Eben, Mirza, Muhammad Bilal, Naveed, Abdullah Bin, Tanaka, Hidenori, Hom, Marisa, Mani, Lucas, Meeks, Nicole

2025

Overview

Erb‐b2 receptor tyrosine kinase 2 (ERBB2; also known as HER2) expression is observed in 25–40% of head and neck squamous cell carcinomas (HNSCC), yet there are no anti‐HER2 therapies under evaluation for HNSCC, as conventional cytostatic anti‐HER2 antibodies have had limited effectiveness and levels of HER2 overexpression are lower in HNSCC tumors compared to breast cancer. Trastuzumab‐deruxtecan (T‐DXd; Enhertu) is a HER2‐targeting antibody‐drug conjugate (ADC) comprising an anti‐HER2 monoclonal antibody, a cleavable linker, and a potent topoisomerase I inhibitor payload, and has shown promising results in very low HER2‐expressing tumors. We compare the efficacy of T‐DXd, trastuzumab‐emtansine (ADC comprising an anti‐HER2 antibody and microtubule inhibitor, T‐DM1; Kadcyla) and trastuzumab (Herceptin) therapy in HNSCC with low and absent HER2 expression in vitro and in vivo. In vitro treatment of a low HER2‐expressing human HNSCC cell line (FaDu) with T‐DXd resulted in dose‐dependent cell death (IC50 values of 9856 ng·mL−1). T‐DXd treatment of FaDu and UMSCC‐47 (low HER2‐expressing cell line) mouse xenografts displayed antitumor activity (P = 0.0001 and 0.015 respectively). When comparing T‐DXd to other approved anti‐HER2 therapies, only FaDu mice treated with T‐DXd showed a reduction in tumor growth (P = 0.0012). In UMSCC‐1 cells (absent HER2 expression), the drug failed to accumulate in tumors and showed no measurable antitumor effect, in contrast to FaDu xenografts, where drug accumulation in the tumor correlated with a therapeutic response. T‐DXd treatment yielded antitumor activity in FaDu and UMSCC‐47 tumors, highlighting the potential for T‐DXd efficacy in low HER2‐expressing tumors. Trastuzumab‐deruxtecan, a HER2‐targeting antibody‐drug conjugate, shows promising antitumor activity in head and neck squamous cell carcinoma with low HER2 expression. In vitro and in vivo studies demonstrated dose‐dependent cell death and tumor growth reduction in low HER2‐expressing cell lines, which correlated with drug accumulation measured using a fluorescent antibody‐drug conjugate.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Animals / antibody‐drug conjugates / Antigens / Antitumor activity / Breast cancer / Camptothecin - analogs & derivatives / Camptothecin - pharmacology / Camptothecin - therapeutic use / Cancer and Oncology / Cancer Therapies / Cell death / Cell Line, Tumor / DNA topoisomerase / drug delivery / Epidermal growth factor / ErbB-2 protein / Erb‐b2 receptor tyrosine kinase 2 / Experiments / Female / Head & neck cancer / Head and Neck Cancer / Head and neck carcinoma / Head and Neck Neoplasms - diagnostic imaging / Head and Neck Neoplasms - drug therapy / Head and Neck Neoplasms - metabolism / Head and Neck Neoplasms - pathology / head and neck squamous cell carcinoma / Humans / Immunoconjugates - pharmacology / Immunoconjugates - therapeutic use / Immunohistochemistry / Kinases / Metastasis / Mice / mice xenograft / Mice, Nude / Molecular Imaging - methods / Monoclonal antibodies / optical imaging / Penicillin / Pharmacy / Protein-tyrosine kinase receptors / Receptor, ErbB-2 - metabolism / Squamous cell carcinoma / Squamous Cell Carcinoma of Head and Neck - drug therapy / Stains & staining / Trastuzumab / Trastuzumab - pharmacology / Trastuzumab - therapeutic use / Tumors / Xenograft Model Antitumor Assays / Xenografts