A proteogenomic portrait of lung squamous cell carcinoma

• Published in: Cell Vol. 184; no. 16; pp. 4348 - 4371.e40
• Main Authors: Satpathy, Shankha, Krug, Karsten, Jean Beltran, Pierre M, Savage, Sara R, Petralia, Francesca, Kumar-Sinha, Chandan, Dou, Yongchao, Reva, Boris, Kane, M Harry, Avanessian, Shayan C, Vasaikar, Suhas V, Krek, Azra, Lei, Jonathan T, Jaehnig, Eric J, Omelchenko, Tatiana, Geffen, Yifat, Bergstrom, Erik J, Stathias, Vasileios, Christianson, Karen E, Heiman, David I, Cieslik, Marcin P, Cao, Song, Song, Xiaoyu, Ji, Jiayi, Liu, Wenke, Li, Kai, Wen, Bo, Li, Yize, Gümüş, Zeynep H, Selvan, Myvizhi Esai, Soundararajan, Rama, Visal, Tanvi H, Raso, Maria G, Parra, Edwin Roger, Babur, Özgün, Vats, Pankaj, Anand, Shankara, Schraink, Tobias, Cornwell, MacIntosh, Rodrigues, Fernanda Martins, Zhu, Houxiang, Mo, Chia-Kuei, Zhang, Yuping, da Veiga Leprevost, Felipe, Huang, Chen, Chinnaiyan, Arul M, Wyczalkowski, Matthew A, Omenn, Gilbert S, Newton, Chelsea J, Schurer, Stephan, Ruggles, Kelly V, Fenyö, David, Jewell, Scott D, Thiagarajan, Mathangi, Mesri, Mehdi, Rodriguez, Henry, Mani, Sendurai A, Udeshi, Namrata D, Getz, Gad, Suh, James, Li, Qing Kay, Hostetter, Galen, Paik, Paul K, Dhanasekaran, Saravana M, Govindan, Ramaswamy, Ding, Li, Robles, Ana I, Clauser, Karl R, Nesvizhskii, Alexey I, Wang, Pei, Carr, Steven A, Zhang, Bing, Mani, D R, Gillette, Michael A
• Format: Journal Article
• Language: English
• Published: United States 05-08-2021
• Subjects: Acetylation; Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell - genetics; Cluster Analysis; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 6 - genetics; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms - genetics; Male; Middle Aged; Mutation - genetics; Neoplasm Proteins - metabolism; Phosphorylation; Protein Binding; Proteogenomics; Receptor Tyrosine Kinase-like Orphan Receptors - metabolism; Receptors, Platelet-Derived Growth Factor - metabolism; Signal Transduction; Ubiquitination; acetylation; lung cancer; squamous; proteomics; protein; genomics; CPTAC; phosphorylation; proteogenomics; ubiquitylation
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2021.07.016

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.