@article{475a89c18d2c47e0a3f539fcc2e01474,
title = "Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma",
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. Huang et al. report a proteogenomic study on 108 HPV-negative head and neck squamous cell carcinomas (HNSCCs). In addition to creating a comprehensive resource for pathogenic insights, multi-omic analysis identifies therapeutic hypotheses that may inform more precise approaches to treatment.",
keywords = "CDK inhibitor, CPTAC, EGFR mAb, HNSCC, combination immune checkpoint blockade, immune evasion, immunotherapy, predictive biomarker, proteogenomics, proteomics",
author = "{Clinical Proteomic Tumor Analysis Consortium} and Chen Huang and Lijun Chen and Savage, {Sara R.} and Eguez, {Rodrigo Vargas} and Yongchao Dou and Yize Li and {da Veiga Leprevost}, Felipe and Jaehnig, {Eric J.} and Lei, {Jonathan T.} and Bo Wen and Michael Schnaubelt and Karsten Krug and Xiaoyu Song and Marcin Cie{\'s}lik and Chang, {Hui Yin} and Wyczalkowski, {Matthew A.} and Kai Li and Antonio Colaprico and Li, {Qing Kay} and Clark, {David J.} and Yingwei Hu and Liwei Cao and Jianbo Pan and Yuefan Wang and Cho, {Kyung Cho} and Zhiao Shi and Yuxing Liao and Wen Jiang and Meenakshi Anurag and Jiayi Ji and Seungyeul Yoo and Zhou, {Daniel Cui} and Liang, {Wen Wei} and Michael Wendl and Pankaj Vats and Carr, {Steven A.} and Mani, {D. R.} and Zhen Zhang and Jiang Qian and Chen, {Xi S.} and Pico, {Alexander R.} and Pei Wang and Chinnaiyan, {Arul M.} and Ketchum, {Karen A.} and Kinsinger, {Christopher R.} and Robles, {Ana I.} and Eunkyung An and Tara Hiltke and Mehdi Mesri and Richard Smith",
note = "Funding Information: This work was supported by grants U24 CA210954, U24 CA210985, U24 CA210972, U24 CA210979, U24 CA210986, U24 CA214125, U24 CA210967, and U24 CA210993 from the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC), by a Cancer Prevention Institute of Texas (CPRIT) award RR160027, by grant T32 CA203690 from the Translational Breast Cancer Research Training Program, and by funding from the McNair Foundation. B.Z. and M.J.E. are CPRIT Scholar in Cancer Research and McNair Medical Institute Scholar. M.J.E. is a Susan G. Komen Foundation Scholar. We thank Christopher J. Rickets (NCI) for helpful discussions. Conceptualization: D.W.C. H.Z. B.Z.; Methodology: C.H. L.C. S.R.S. R.V.E. Y.D. Y.L. E.J.J. M.S. K.K. M.C. H.C. B.W. K.L. D.J.C. Y.H. L.C. Y.W. Z.S. M.A. M.W. D.R.M. S.S. M.A.G. L.D. A.I.N. H.Z. B.Z.; Software: F.d.V.L. M.S. K.K. H.C. B.W. K.L. Y.H. J.P. K.C. Z.S. Y.L. J.Q. A.I.N.; Validation: L.C. R.V.E. M.S. D.J.C. Y.H. L.C. Y.W. G.M. H.Z.; Formal Analysis: C.H. S.R.S. Y.D. Y.L. F.d.V.L. E.J.J. K.K. X.S. M.C. H.C. M.A.W. B.W. J.T.L. K.L. A.C. Y.H. J.P. Z.S. W.J. M.A. J.J. D.C.Z. W.L. P.V. D.R.M. J.Q. S.S. M.A.G. S.M.D. B.Z.; Investigation: C.H. L.C. S.R.S. R.V.E. Y.D. Y.L. F.d.V.L. E.J.J. M.S. K.K. J.T.L. Q.K.L. D.J.C. Y.H. L.C. J.P. Y.W. W.J. M.A. S.Y. P.V. Z.Z. J.Q. M.J.E. G.S.O. S.M.D. L.D. A.I.N. A.K.E. D.W.C. H.Z. B.Z.; Resources: L.C. M.S. B.W. K.L. Q.K.L. Y.H. J.P. Y.W. Z.S. Y.L. D.R.M. J.Q. X.S.C. G.M. H.Z. B.Z.; Data curation: C.H. L.C. R.V.E. Q.K.L. D.J.C. L.C. Y.W. K.A.K. S.M.D. H.Z.; Writing – Original Drafts: C.H. L.C. S.R.S. Y.D. Y.L. F.d.V.L. E.J.J. M.S. B.W. J.T.L. K.L. Y.H. Z.S. W.J. L.D. A.K.E. H.Z. B.Z.; Writing – Review & Editing: C.H. S.R.S. Y.D. Y.L. E.J.J. K.K. J.T.L. A.C. D.R.M. A.R.P. A.M.C. E.A. A.M.W. J.L. M.W. M.W. A.S. S.S. M.A.G. G.S.O. E.S.B. S.M.D. L.D. A.I.N. A.K.E. H.Z. B.Z.; Visualization: C.H. S.R.S. Y.D. Y.L. E.J.J. K.K. X.S. J.T.L. Q.K.L. Y.H. J.P. J.J. B.Z.; Supervision: S.A.C. D.R.M. Z.Z. J.Q. X.S.C. P.W. A.M.C. S.M.D. L.D. A.I.N. D.W.C. H.Z. B.Z.; Project administration: Z.Z. J.Q. C.R.K. A.I.R. E.A. T.H. M.M. M.T. H.R. E.S.B. D.W.C. H.Z. B.Z.; Funding acquisition: S.A.C. D.R.M. Z.Z. P.W. A.M.C. A.I.N. D.W.C. H.Z. B.Z. S.A.C. is a member of the scientific advisory boards of Kymera, PTM BioLabs, and Seer and a scientific advisor to Pfizer and Biogen. The other authors have no conflicts of interest to declare. M.J.E. reports ownership and royalties associated with Bioclassifier LLC through sales by Nanostring LLC and Veracyte for the “Prosigna” breast cancer prognostic test. M.J.E. also reports ad hoc consulting for AstraZeneca, Foundation Medicine, G1 Therapeutics, Novartis, Sermonix, Abbvie, Lilly and Pfizer. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = mar,
day = "8",
doi = "10.1016/j.ccell.2020.12.007",
language = "English (US)",
volume = "39",
pages = "361--379.e16",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "3",
}
