A proteogenomic portrait of lung squamous cell carcinoma.

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From: Cell(Vol. 184, Issue 16)
Publisher: Elsevier B.V.
Document Type: Report
Length: 1,011 words

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Keywords lung cancer; squamous; proteogenomics; proteomics; genomics; protein; phosphorylation; acetylation; ubiquitylation; CPTAC Highlights * Unsupervised clustering revealed subtype with EMT and phosphoprotein signatures * Potential therapeutic vulnerabilities included survivin, NSD3, LSD1, and EZH2 * Rb phosphorylation nominated as a biomarker for trials with CDK4/6 inhibitors * Detailed immune landscape analysis highlighted targetable points of immuneregulation Summary Lung squamous cell carcinoma (LSCC) remains a leading cause of cancer death with few therapeutic options. We characterized the proteogenomic landscape of LSCC, providing a deeper exposition of LSCC biology with potential therapeutic implications. We identify NSD3 as an alternative driver in FGFR1-amplified tumors and low-p63 tumors overexpressing the therapeutic target survivin. SOX2 is considered undruggable, but our analyses provide rationale for exploring chromatin modifiers such as LSD1 and EZH2 to target SOX2-overexpressing tumors. Our data support complex regulation of metabolic pathways by crosstalk between post-translational modifications including ubiquitylation. Numerous immune-related proteogenomic observations suggest directions for further investigation. Proteogenomic dissection of CDKN2A mutations argue for more nuanced assessment of RB1 protein expression and phosphorylation before declaring CDK4/6 inhibition unsuccessful. Finally, triangulation between LSCC, LUAD, and HNSCC identified both unique and common therapeutic vulnerabilities. These observations and proteogenomics data resources may guide research into the biology and treatment of LSCC. Author Affiliation: (1) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA (2) Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA (3) Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA (4) Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA (5) Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (6) Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA (7) Sylvester Comprehensive Cancer Center and Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA (8) Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA (9) Department of Population Health Science and Policy, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA (10) Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA (11) Computer Science Department, University of Massachusetts Boston, Boston, MA 02125, USA (12) Institute for Systems Genetics and Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA (13) Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA (14) Van Andel Research Institute, Grand Rapids, MI 49503, USA (15) Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA (16) Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA (17) Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA (18) Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02115, USA * Corresponding author Article History: Received 6 November 2020; Revised 26 April 2021; Accepted 12 July 2021 (miscellaneous) Published: August 5, 2021 (footnote)19 These authors contributed equally (footnote)20 These authors contributed equally (footnote)21 Lead contact Byline: Shankha Satpathy [shankha@broadinstitute.org] (1,19,*), Karsten Krug (1,19), Pierre M. Jean Beltran (1,19), Sara R. Savage (2,19), Francesca Petralia (3,20), Chandan Kumar-Sinha (4,20), Yongchao Dou (2,20), Boris Reva (3,20), M. Harry Kane (1,20), Shayan C. Avanessian (1,20), Suhas V. Vasaikar (5,20), Azra Krek (3), Jonathan T. Lei (2), Eric J. Jaehnig (2), Tatiana Omelchenko (6), Yifat Geffen (1), Erik J. Bergstrom (1), Vasileios Stathias (7), Karen E. Christianson (1), David I. Heiman (1), Marcin P. Cieslik (4,13), Song Cao (8), Xiaoyu Song (9), Jiayi Ji (9), Wenke Liu (10), Kai Li (2), Bo Wen (2), Yize Li (8), Zeynep H. Gümüs (3), Myvizhi Esai Selvan (3), Rama Soundararajan (5), Tanvi H. Visal (5), Maria G. Raso (5), Edwin Roger Parra (5), Özgün Babur (11), Pankaj Vats (4), Shankara Anand (1), Tobias Schraink (12), MacIntosh Cornwell (12), Fernanda Martins Rodrigues (8), Houxiang Zhu (8), Chia-Kuei Mo (8), Yuping Zhang (4), Felipe da Veiga Leprevost (4), Chen Huang (2), Arul M. Chinnaiyan (4), Matthew A. Wyczalkowski (8), Gilbert S. Omenn (13), Chelsea J. Newton (14), Stephan Schurer (7), Kelly V. Ruggles (12), David Fenyö (10), Scott D. Jewell (14), Mathangi Thiagarajan (15), Mehdi Mesri (16), Henry Rodriguez (16), Sendurai A. Mani (5), Namrata D. Udeshi (1), Gad Getz (1), James Suh (15), Qing Kay Li (17), Galen Hostetter (14), Paul K. Paik (6), Saravana M. Dhanasekaran (4), Ramaswamy Govindan (8), Li Ding (8), Ana I. Robles (16), Karl R. Clauser (1), Alexey I. Nesvizhskii (4,13), Pei Wang (3), Steven A. Carr [scarr@broad.mit.edu] (1,**), Bing Zhang [bing.zhang@bcm.edu] (2,***), D.R. Mani [manidr@broadinstitute.org] (1,****), Michael A. Gillette [gillette@broadinstitute.org] (1,18,21,*****), Alex Green, Alfredo Molinolo, Alicia Francis, Amanda G. Paulovich, Andrii Karnuta, Antonio Colaprico, Barbara Hindenach, Barbara L. Pruetz, Bartosz Kubisa, Brian J. Druker, Carissa Huynh, Charles A. Goldthwaite Jr., Chet Birger, Christopher R. Kinsinger, Corbin D. Jones, Dan Rohrer, Dana R. Valley, Daniel W. Chan, David Chesla, Donna Hansel, Elena V. Ponomareva, Elizabeth Duffy, Eric Burks, Eric E. Schadt, Eugene S. Fedorov, Eunkyung An, Fei Ding, George D. Wilson, Harsh Batra, Hui Zhang, Jennifer E. Maas, Jennifer Eschbacher, Karen A. Ketchum, Karin D. Rodland, Katherine A. Hoadley, Kei Suzuki, Ki Sung Um, Liqun Qi, Lori Bernard, Maciej Wiznerowicz, Malgorzata Wojtys, Marcin J. Domagalski, Matthew J. Ellis, Maureen A. Dyer, Melissa Borucki, Meenakshi Anurag, Michael J. Birrer, Midie Xu, Mikhail Krotevich, Nancy Roche, Nathan J. Edwards, Negin Vatanian, Neil R. Mucci, Nicollette Maunganidze, Nikolay Gabrovski, Olga Potapova, Oluwole Fadare, Pamela Grady, Peter B. McGarvey, Pushpa Hariharan, Ratna R. Thangudu, Rebecca Montgomery, Renganayaki Pandurengan, Richard D. Smith, Robert J. Welsh, Sailaja Mareedu, Samuel H. Payne, Sandra Cottingham, Shilpi Singh, Shirley X. Tsang, Shuang Cai, Stacey Gabriel, Tao Liu, Tara Hiltke, Tanmayi Vashist, Thomas Bauer, Volodymyr Sovenko, Warren G. Tourtellotte, Weiping Ma, William Bocik, Wohaib Hasan, Xiaojun Jing, Ximing Tang, Yuxing Liao, Yvonne, Shutack, Zhen Zhang, Ziad Hanhan

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Gale Document Number: GALE|A670935668