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Mechanobiology

Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma

AUTHORS

Huang CChen , Chen LLijun , Savage SRSara R , Eguez RVRodrigo Vargas , Dou YYongchao , Li YYize , da Veiga Leprevost FFelipe , Jaehnig EJEric J , Lei JTJonathan T , Wen BBo , Schnaubelt MMichael , Krug KKarsten , Song XXiaoyu , Cieślik MMarcin , Chang HYHui-Yin , Wyczalkowski MAMatthew A , Li KKai , Colaprico AAntonio , Li QKQing Kay , Clark DJDavid J , Hu YYingwei , Cao LLiwei , Pan JJianbo , Wang YYuefan , Cho KCKyung-Cho , Shi ZZhiao , Liao YYuxing , Jiang WWen , Anurag MMeenakshi , Ji JJiayi , Yoo SSeungyeul , Zhou DCDaniel Cui , Liang WWWen-Wei , Wendl MMichael , Vats PPankaj , Carr SASteven A , Mani DRD R , Zhang ZZhen , Qian JJiang , Chen XSXi S , Pico ARAlexander R , Wang PPei , Chinnaiyan AMArul M , Ketchum KAKaren A , Kinsinger CRChristopher R , Robles AIAna I , An EEunkyung , Hiltke TTara , Mesri MMehdi , Thiagarajan MMathangi , Weaver AMAlissa M , Sikora AGAndrew G , Lubiński JJan , Wierzbicka MMałgorzata , Wiznerowicz MMaciej , Satpathy SShankha , Gillette MAMichael A , Miles GGeorge , Ellis MJMatthew J , Omenn GSGilbert S , Rodriguez HHenry , Boja ESEmily S , Dhanasekaran SMSaravana M , Ding LLi , Nesvizhskii AIAlexey I , El-Naggar AKAdel K , Chan DWDaniel W , Zhang HHui , Zhang BBing , . Cancer cell. 2021 1 7; 39(3). 361-379.e16

ABSTRACT

We present a proteogenomic study of 108 human papilloma virus (HPV)-negative head and neck squamous cell carcinomas (HNSCCs). Proteomic analysis systematically catalogs HNSCC-associated proteins and phosphosites, prioritizes copy number drivers, and highlights an oncogenic role for RNA processing genes. Proteomic investigation of mutual exclusivity between FAT1 truncating mutations and 11q13.3 amplifications reveals dysregulated actin dynamics as a common functional consequence. Phosphoproteomics characterizes two modes of EGFR activation, suggesting a new strategy to stratify HNSCCs based on EGFR ligand abundance for effective treatment with inhibitory EGFR monoclonal antibodies. Widespread deletion of immune modulatory genes accounts for low immune infiltration in immune-cold tumors, whereas concordant upregulation of multiple immune checkpoint proteins may underlie resistance to anti-programmed cell death protein 1 monotherapy in immune-hot tumors. Multi-omic analysis identifies three molecular subtypes with high potential for treatment with CDK inhibitors, anti-EGFR antibody therapy, and immunotherapy, respectively. Altogether, proteogenomics provides a systematic framework to inform HNSCC biology and treatment.