Clinical utility of PDX cohorts to reveal biomarkers of intrinsic resistance and clonal architecture changes underlying acquired resistance to cetuximab in HNSCC

• DOI: 10.1038/s41392-022-00908-0
• Publication Date: 2022-03-08T10:03:34Z
• Authors: Yanli Yao; Yujue Wang; Lan Chen; Zhen Tian; Guizhu Yang; Rui Wang; Chong Wang; Qi Wu; Yaping Wu; Jiamin Gao; Xindan Kang; Shengzhong Duan; Zhiyuan Zhang; Shuyang Sun
• Keywords: 0301 basic medicine; QH301-705.5; Squamous Cell Carcinoma of Head and Neck; R; Cetuximab; Article; 3. Good health; 03 medical and health sciences; Drug Resistance, Neoplasm; Head and Neck Neoplasms; Medicine; Humans; Biology (General); Biomarkers

Abstract Cetuximab is a widely used drug for treating head and neck squamous cell carcinomas (HNSCCs); however, it provides restricted clinical benefits, its response duration limited by resistance. Here, we conducted randomized “Phase II-like trials” of 49 HNSCC PDX models reveal multiple informative biomarkers intrinsic resistance to cetuximab (e.g., amplification ANKH , up-regulation PARP3). After validating these in another cohort (61 models), generated acquired analyzed them uncover mechanisms. Whole exome sequencing transcriptome revealed diverse patterns clonal selection resistant PDXs, including the emergence subclones with strongly activated RAS/MAPK. Extending insights, show that combination RAC1/RAC3 dual-target inhibitor could overcome vitro vivo. Beyond revealing biomarkers, our PDX-based study shows how architecture changes underlying can be targeted expand therapeutic utility this important more patients.