Journal
CANCER CELL
Volume 39, Issue 3, Pages 361-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2020.12.007
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Funding
- National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) [U24 CA210954, U24 CA210985, U24 CA210972, U24 CA210979, U24 CA210986, U24 CA214125, U24 CA210967, U24 CA210993]
- Cancer Prevention Institute of Texas (CPRIT) [RR160027]
- Translational Breast Cancer Research Training Program [T32 CA203690]
- McNair Foundation
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This study presents a proteogenomic analysis of HPV-negative HNSCCs, identifying potential therapeutic targets and uncovering tumor characteristics such as immune status and resistance mechanisms. The findings suggest new strategies for stratifying HNSCC and improving treatment outcomes.
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 phospho-sites, 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 dys-regulated 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 mono-therapy 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, pro-teogenomics provides a systematic framework to inform HNSCC biology and treatment.
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