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

Academic Article

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.

    • Authors

    Published In

  • Cancer Cell  Journal

    • Keywords

  • CDK inhibitor, CPTAC, EGFR mAb, HNSCC, combination immune checkpoint blockade, immune evasion, immunotherapy, predictive biomarker, proteogenomics, proteomics, Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological, ErbB Receptors, Female, Humans, Immunotherapy, Male, Middle Aged, Papillomavirus Infections, Proteogenomics, Proteomics, Squamous Cell Carcinoma of Head and Neck, Young Adult

    • Digital Object Identifier (doi)

    Author List

  • Huang C; Chen L; Savage SR; Eguez RV; Dou Y; Li Y; da Veiga Leprevost F; Jaehnig EJ; Lei JT; Wen B

    • Start Page

  • 361

    • End Page

  • 379.e16

    • Volume

  • 39

    • Issue

  • 3