Pharmacogenomic landscape of head and neck squamous cell carcinoma informs precision oncology therapy

• DOI: 10.1126/scitranslmed.abo5987
• Publication Date: 2022-09-07T17:58:12Z
• Authors: Ziyue Gu; Yanli Yao; Guizhu Yang; Guopei Zhu; Zhen Tian; Rui Wang; Qi Wu; Yujue Wang; Yaping Wu; Lan Chen; Chong Wang; Jiamin Gao; Xindan Kang; Jie Zhang; Lizhen Wang; Shengzhong Duan; Zhongming Zhao; Zhiyuan Zhang; Shuyang Sun
• Keywords: 0303 health sciences; 03 medical and health sciences; Head and Neck Neoplasms; Pharmacogenetics; Squamous Cell Carcinoma of Head and Neck; Humans; Docetaxel; Precision Medicine; 3. Good health

Head and neck squamous cell carcinoma (HNSCC) is a common and frequently lethal cancer with few therapeutic options. In particular, there are few effective targeted therapies. Development of highly effective therapeutic strategies tailored to patients with HNSCC remains a pressing challenge. To address this, we present a pharmacogenomic study to facilitate precision treatments for patients with HNSCC. We established a large collection of 56 HNSCC patient-derived cells (PDCs), which recapitulated the molecular features of the original tumors. Pharmacological assessment of HNSCCs was conducted using a three-tiered high-throughput drug screening using 2248 compounds across these PDC models and an additional 18 immortalized cell lines. We integrated genomic, transcriptomic, and pharmacological analysis to predict biomarkers, gene-drug associations, and validated biomarkers. These results supported drug repurposing for multiple HNSCC subtypes, including the JAK2 inhibitor fedratinib, for low KRT18 –expressing HNSCC cases, and the topoisomerase inhibitor mitoxantrone, for IL6R -activated HNSCC cases. Our results demonstrated concordance between susceptibility predictions from the PDCs and the matched patients’ responses to standard clinical medication. Moreover, we identified and experimentally confirmed that high expression of ITGB1 elicited therapeutic resistance to docetaxel and high SOD1 expression conferred resistance to afatinib. We further validated ITGB1 as a predictive biomarker for the efficacy of docetaxel therapy in a phase 2 clinical trial. In summary, our study shows that this HNSCC cell resource, as well as the resulting pharmacogenomic profiles, is effective for biomarker discovery and for guiding precision oncology therapies in HNSCCs.