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

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

doi:10.1038/s41392-022-00908-0

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

Signal Transduct Target Ther. 2022 Mar 8;7(1):73. doi: 10.1038/s41392-022-00908-0.

Authors

Yanli Yao^#^{1

2}, Yujue Wang^#^{1

2}, Lan Chen^#^{1

2}, Zhen Tian^{2

3}, Guizhu Yang^{1

2}, Rui Wang^{1

2}, Chong Wang^{1

2}, Qi Wu^{1

2}, Yaping Wu^{1

2}, Jiamin Gao^{1

2}, Xindan Kang^{1

2}, Shengzhong Duan^{2

4}, Zhiyuan Zhang^{5

6}, Shuyang Sun^{7

8}

Affiliations

¹ Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China.
³ Department of Oral Pathology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁴ Laboratory of Oral Microbiota and Systemic Diseases, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. zhzhy@sjtu.edu.cn.
⁶ College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China. zhzhy@sjtu.edu.cn.
⁷ Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. sunshuyang@sjtu.edu.cn.
⁸ College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology, Shanghai, China. sunshuyang@sjtu.edu.cn.

^# Contributed equally.

Abstract

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

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
Cetuximab / pharmacology
Drug Resistance, Neoplasm* / genetics
Head and Neck Neoplasms* / drug therapy
Head and Neck Neoplasms* / genetics
Humans
Squamous Cell Carcinoma of Head and Neck* / drug therapy
Squamous Cell Carcinoma of Head and Neck* / genetics

Substances

Biomarkers
Cetuximab