PMID- 34358469 OWN - NLM STAT- MEDLINE DCOM- 20220105 LR - 20230921 IS - 1097-4172 (Electronic) IS - 0092-8674 (Print) IS - 0092-8674 (Linking) VI - 184 IP - 16 DP - 2021 Aug 5 TI - A proteogenomic portrait of lung squamous cell carcinoma. PG - 4348-4371.e40 LID - S0092-8674(21)00857-6 [pii] LID - 10.1016/j.cell.2021.07.016 [doi] AB - 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. CI - Copyright (c) 2021 The Author(s). Published by Elsevier Inc. All rights reserved. FAU - Satpathy, Shankha AU - Satpathy S AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: shankha@broadinstitute.org. FAU - Krug, Karsten AU - Krug K AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Jean Beltran, Pierre M AU - Jean Beltran PM AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Savage, Sara R AU - Savage SR AD - Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Petralia, Francesca AU - Petralia F AD - 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. FAU - Kumar-Sinha, Chandan AU - Kumar-Sinha C AD - Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Dou, Yongchao AU - Dou Y AD - Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Reva, Boris AU - Reva B AD - 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. FAU - Kane, M Harry AU - Kane MH AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Avanessian, Shayan C AU - Avanessian SC AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Vasaikar, Suhas V AU - Vasaikar SV AD - Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Krek, Azra AU - Krek A AD - 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. FAU - Lei, Jonathan T AU - Lei JT AD - Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Jaehnig, Eric J AU - Jaehnig EJ AD - Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Omelchenko, Tatiana AU - Omelchenko T AD - Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Geffen, Yifat AU - Geffen Y AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Bergstrom, Erik J AU - Bergstrom EJ AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Stathias, Vasileios AU - Stathias V AD - Sylvester Comprehensive Cancer Center and Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. FAU - Christianson, Karen E AU - Christianson KE AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Heiman, David I AU - Heiman DI AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Cieslik, Marcin P AU - Cieslik MP AD - Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Cao, Song AU - Cao S AD - Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA. FAU - Song, Xiaoyu AU - Song X AD - Department of Population Health Science and Policy, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Ji, Jiayi AU - Ji J AD - Department of Population Health Science and Policy, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. FAU - Liu, Wenke AU - Liu W AD - Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA. FAU - Li, Kai AU - Li K AD - Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Wen, Bo AU - Wen B AD - Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Li, Yize AU - Li Y AD - Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA. FAU - Gumus, Zeynep H AU - Gumus ZH AD - 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. FAU - Selvan, Myvizhi Esai AU - Selvan ME AD - 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. FAU - Soundararajan, Rama AU - Soundararajan R AD - Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Visal, Tanvi H AU - Visal TH AD - Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Raso, Maria G AU - Raso MG AD - Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Parra, Edwin Roger AU - Parra ER AD - Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Babur, Ozgun AU - Babur O AD - Computer Science Department, University of Massachusetts Boston, Boston, MA 02125, USA. FAU - Vats, Pankaj AU - Vats P AD - Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Anand, Shankara AU - Anand S AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Schraink, Tobias AU - Schraink T AD - Institute for Systems Genetics and Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA. FAU - Cornwell, MacIntosh AU - Cornwell M AD - Institute for Systems Genetics and Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA. FAU - Rodrigues, Fernanda Martins AU - Rodrigues FM AD - Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA. FAU - Zhu, Houxiang AU - Zhu H AD - Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA. FAU - Mo, Chia-Kuei AU - Mo CK AD - Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA. FAU - Zhang, Yuping AU - Zhang Y AD - Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. FAU - da Veiga Leprevost, Felipe AU - da Veiga Leprevost F AD - Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Huang, Chen AU - Huang C AD - Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. FAU - Chinnaiyan, Arul M AU - Chinnaiyan AM AD - Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Wyczalkowski, Matthew A AU - Wyczalkowski MA AD - Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA. FAU - Omenn, Gilbert S AU - Omenn GS AD - Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Newton, Chelsea J AU - Newton CJ AD - Van Andel Research Institute, Grand Rapids, MI 49503, USA. FAU - Schurer, Stephan AU - Schurer S AD - Sylvester Comprehensive Cancer Center and Department of Molecular and Cellular Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA. FAU - Ruggles, Kelly V AU - Ruggles KV AD - Institute for Systems Genetics and Department of Medicine, NYU Grossman School of Medicine, New York, NY 10016, USA. FAU - Fenyo, David AU - Fenyo D AD - Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA. FAU - Jewell, Scott D AU - Jewell SD AD - Van Andel Research Institute, Grand Rapids, MI 49503, USA. FAU - Thiagarajan, Mathangi AU - Thiagarajan M AD - Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. FAU - Mesri, Mehdi AU - Mesri M AD - Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA. FAU - Rodriguez, Henry AU - Rodriguez H AD - Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA. FAU - Mani, Sendurai A AU - Mani SA AD - Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Udeshi, Namrata D AU - Udeshi ND AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Getz, Gad AU - Getz G AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Suh, James AU - Suh J AD - Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. FAU - Li, Qing Kay AU - Li QK AD - Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21224, USA. FAU - Hostetter, Galen AU - Hostetter G AD - Van Andel Research Institute, Grand Rapids, MI 49503, USA. FAU - Paik, Paul K AU - Paik PK AD - Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Dhanasekaran, Saravana M AU - Dhanasekaran SM AD - Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Govindan, Ramaswamy AU - Govindan R AD - Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA. FAU - Ding, Li AU - Ding L AD - Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO 63110, USA. FAU - Robles, Ana I AU - Robles AI AD - Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA. FAU - Clauser, Karl R AU - Clauser KR AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. FAU - Nesvizhskii, Alexey I AU - Nesvizhskii AI AD - Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Wang, Pei AU - Wang P AD - 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. FAU - Carr, Steven A AU - Carr SA AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: scarr@broad.mit.edu. FAU - Zhang, Bing AU - Zhang B AD - Lester and Sue Smith Breast Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: bing.zhang@bcm.edu. FAU - Mani, D R AU - Mani DR AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: manidr@broadinstitute.org. FAU - Gillette, Michael A AU - Gillette MA AD - Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA 02115, USA. Electronic address: gillette@broadinstitute.org. CN - Clinical Proteomic Tumor Analysis Consortium LA - eng GR - U24 CA210954/CA/NCI NIH HHS/United States GR - U01 CA214116/CA/NCI NIH HHS/United States GR - U24 CA210985/CA/NCI NIH HHS/United States GR - F32 HL154711/HL/NHLBI NIH HHS/United States GR - U24 CA210967/CA/NCI NIH HHS/United States GR - U54 HL127624/HL/NHLBI NIH HHS/United States GR - U24 CA210986/CA/NCI NIH HHS/United States GR - U24 CA210972/CA/NCI NIH HHS/United States GR - U24 CA210955/CA/NCI NIH HHS/United States GR - U24 CA210993/CA/NCI NIH HHS/United States GR - K26 RR026099/RR/NCRR NIH HHS/United States GR - T32 CA203690/CA/NCI NIH HHS/United States GR - R01 NS095894/NS/NINDS NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - K26 OD010945/OD/NIH HHS/United States GR - P30 CA240139/CA/NCI NIH HHS/United States GR - U24 CA210979/CA/NCI NIH HHS/United States GR - U01 CA214114/CA/NCI NIH HHS/United States GR - U01 CA214125/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - Cell JT - Cell JID - 0413066 RN - 0 (Neoplasm Proteins) RN - EC 2.7.10.1 (ROR2 protein, human) RN - EC 2.7.10.1 (Receptor Tyrosine Kinase-like Orphan Receptors) RN - EC 2.7.10.1 (Receptors, Platelet-Derived Growth Factor) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 4) RN - EC 2.7.11.22 (Cyclin-Dependent Kinase 6) SB - IM MH - Acetylation MH - Adult MH - Aged MH - Aged, 80 and over MH - Carcinoma, Squamous Cell/*genetics MH - Cluster Analysis MH - Cyclin-Dependent Kinase 4/genetics MH - Cyclin-Dependent Kinase 6/genetics MH - Epithelial-Mesenchymal Transition/genetics MH - Female MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Lung Neoplasms/*genetics MH - Male MH - Middle Aged MH - Mutation/genetics MH - Neoplasm Proteins/metabolism MH - Phosphorylation MH - Protein Binding MH - *Proteogenomics MH - Receptor Tyrosine Kinase-like Orphan Receptors/metabolism MH - Receptors, Platelet-Derived Growth Factor/metabolism MH - Signal Transduction MH - Ubiquitination PMC - PMC8475722 MID - NIHMS1730863 OTO - NOTNLM OT - CPTAC OT - acetylation OT - genomics OT - lung cancer OT - phosphorylation OT - protein OT - proteogenomics OT - proteomics OT - squamous OT - ubiquitylation COIS- Declaration of interests The authors declare no competing interests. FIR - Green, Alex IR - Green A FIR - Molinolo, Alfredo IR - Molinolo A FIR - Francis, Alicia IR - Francis A FIR - Paulovich, Amanda G IR - Paulovich AG FIR - Karnuta, Andrii IR - Karnuta A FIR - Colaprico, Antonio IR - Colaprico A FIR - Hindenach, Barbara IR - Hindenach B FIR - Pruetz, Barbara L IR - Pruetz BL FIR - Kubisa, Bartosz IR - Kubisa B FIR - Druker, Brian J IR - Druker BJ FIR - Huynh, Carissa IR - Huynh C FIR - Goldthwaite, Charles A Jr IR - Goldthwaite CA Jr FIR - Birger, Chet IR - Birger C FIR - Kinsinger, Christopher R IR - Kinsinger CR FIR - Jones, Corbin D IR - Jones CD FIR - Rohrer, Dan IR - Rohrer D FIR - Valley, Dana R IR - Valley DR FIR - Chan, Daniel W IR - Chan DW FIR - Chesla, David IR - Chesla D FIR - Hansel, Donna IR - Hansel D FIR - Ponomareva, Elena V IR - Ponomareva EV FIR - Duffy, Elizabeth IR - Duffy E FIR - Burks, Eric IR - Burks E FIR - Schadt, Eric E IR - Schadt EE FIR - Fedorov, Eugene S IR - Fedorov ES FIR - An, Eunkyung IR - An E FIR - Ding, Fei IR - Ding F FIR - Wilson, George D IR - Wilson GD FIR - Batra, Harsh IR - Batra H FIR - Zhang, Hui IR - Zhang H FIR - Maas, Jennifer E IR - Maas JE FIR - Eschbacher, Jennifer IR - Eschbacher J FIR - Ketchum, Karen A IR - Ketchum KA FIR - Rodland, Karin D IR - Rodland KD FIR - Hoadley, Katherine A IR - Hoadley KA FIR - Suzuki, Kei IR - Suzuki K FIR - Um, Ki Sung IR - Um KS FIR - Qi, Liqun IR - Qi L FIR - Bernard, Lori IR - Bernard L FIR - Wiznerowicz, Maciej IR - Wiznerowicz M FIR - Wojtys, Malgorzata IR - Wojtys M FIR - Domagalski, Marcin J IR - Domagalski MJ FIR - Ellis, Matthew J IR - Ellis MJ FIR - Dyer, Maureen A IR - Dyer MA FIR - Borucki, Melissa IR - Borucki M FIR - Anurag, Meenakshi IR - Anurag M FIR - Birrer, Michael J IR - Birrer MJ FIR - Xu, Midie IR - Xu M FIR - Krotevich, Mikhail IR - Krotevich M FIR - Roche, Nancy IR - Roche N FIR - Edwards, Nathan J IR - Edwards NJ FIR - Vatanian, Negin IR - Vatanian N FIR - Mucci, Neil R IR - Mucci NR FIR - Maunganidze, Nicollette IR - Maunganidze N FIR - Gabrovski, Nikolay IR - Gabrovski N FIR - Potapova, Olga IR - Potapova O FIR - Fadare, Oluwole IR - Fadare O FIR - Grady, Pamela IR - Grady P FIR - McGarvey, Peter B IR - McGarvey PB FIR - Hariharan, Pushpa IR - Hariharan P FIR - Thangudu, Ratna R IR - Thangudu RR FIR - Montgomery, Rebecca IR - Montgomery R FIR - Pandurengan, Renganayaki IR - Pandurengan R FIR - Smith, Richard D IR - Smith RD FIR - Welsh, Robert J IR - Welsh RJ FIR - Mareedu, Sailaja IR - Mareedu S FIR - Payne, Samuel H IR - Payne SH FIR - Cottingham, Sandra IR - Cottingham S FIR - Singh, Shilpi IR - Singh S FIR - Tsang, Shirley X IR - Tsang SX FIR - Cai, Shuang IR - Cai S FIR - Gabriel, Stacey IR - Gabriel S FIR - Liu, Tao IR - Liu T FIR - Hiltke, Tara IR - Hiltke T FIR - Vashist, Tanmayi IR - Vashist T FIR - Bauer, Thomas IR - Bauer T FIR - Sovenko, Volodymyr IR - Sovenko V FIR - Tourtellotte, Warren G IR - Tourtellotte WG FIR - Ma, Weiping IR - Ma W FIR - Bocik, William IR - Bocik W FIR - Hasan, Wohaib IR - Hasan W FIR - Jing, Xiaojun IR - Jing X FIR - Tang, Ximing IR - Tang X FIR - Liao, Yuxing IR - Liao Y FIR - Yvonne IR - Yvonne FIR - Shutack IR - Shutack FIR - Zhang, Zhen IR - Zhang Z FIR - Hanhan, Ziad IR - Hanhan Z EDAT- 2021/08/07 06:00 MHDA- 2022/01/06 06:00 PMCR- 2022/08/05 CRDT- 2021/08/06 20:09 PHST- 2020/11/06 00:00 [received] PHST- 2021/04/26 00:00 [revised] PHST- 2021/07/12 00:00 [accepted] PHST- 2021/08/06 20:09 [entrez] PHST- 2021/08/07 06:00 [pubmed] PHST- 2022/01/06 06:00 [medline] PHST- 2022/08/05 00:00 [pmc-release] AID - S0092-8674(21)00857-6 [pii] AID - 10.1016/j.cell.2021.07.016 [doi] PST - ppublish SO - Cell. 2021 Aug 5;184(16):4348-4371.e40. doi: 10.1016/j.cell.2021.07.016.