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.
Recommended citation: Satpathy S, Krug K, Jean Beltran PM, Savage SR, Petralia F, Kumar-Sinha C, Dou Y, Reva B, Kane MH, Avanessian SC, Vasaikar SV, Krek A, Lei JT, Jaehnig EJ, Omelchenko T, Geffen Y, Bergstrom EJ, Stathias V, Christianson KE, Heiman DI, Cieslik MP, Cao S, Song X, Ji J, Liu W, Li K, Wen B, Li Y, Gümüş ZH, Selvan ME, Soundararajan R, Visal TH, Raso MG, Parra ER, Babur Ö, Vats P, Anand S, Schraink T, Cornwell M, Rodrigues FM, Zhu H, Mo CK, Zhang Y, da Veiga Leprevost F, Huang C, Chinnaiyan AM, Wyczalkowski MA, Omenn GS, Newton CJ, Schurer S, Ruggles KV, Fenyö D, Jewell SD, Thiagarajan M, Mesri M, Rodriguez H, Mani SA, Udeshi ND, Getz G, Suh J, Li QK, Hostetter G, Paik PK, Dhanasekaran SM, Govindan R, Ding L, Robles AI, Clauser KR, Nesvizhskii AI, Wang P, Carr SA, Zhang B, Mani DR, Gillette MA; Clinical Proteomic Tumor Analysis Consortium. A proteogenomic portrait of lung squamous cell carcinoma. Cell. 2021 Aug 5;184(16):4348-4371.e40. doi: 10.1016/j.cell.2021.07.016. PMID: 34358469.