Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma
Michael A. Gillette, Shankha Satpathy, Song Cao, Saravana M. Dhanasekaran, Suhas Vasaikar, Karsten Krug, Francesca Petralia, Yize Li, Wen-Wei Liang, Boris Reva, Azra Krek, Jiayi Ji, Xiaoyu Song, Wenke Liu, Runyu Hong, Lijun Yao, Lili M. Blumenberg, Sara R. Savage, Michael C. Wendl, Bo Wen, Kai Li, Lauren C. Tang, Melanie A. MacMullan, Shayan C. Avanessian, M. Harry Kane, Chelsea J. Newton, MacIntosh Cornwell, Ramani Kothadia, Weiping Ma, Seungyeul Yoo, Rahul Mannan, Pankaj Vats, Chandan Kumar‐Sinha, Emily Kawaler, Tatiana Omelchenko, Antonio Colaprico, Yifat Geffen, Yosef E. Maruvka, Felipe da Veiga Leprevost, Maciej Wiznerowicz, Zeynep H. Gümüş, Rajwanth Veluswamy, Galen Hostetter, David I. Heiman, Matthew A. Wyczalkowski, Tara Hiltke, Mehdi Mesri, Christopher R. Kinsinger, Emily S. Boja, Gilbert S. Omenn, Arul M. Chinnaiyan, Henry Rodriguez, Qing Kay Li, Scott D. Jewell, Mathangi Thiagarajan, Gad Getz, Bing Zhang, David Fenyö, Kelly V. Ruggles, Marcin Cieślik, Ana I. Robles, Karl R. Clauser, Ramaswamy Govindan, Pei Wang, Alexey I. Nesvizhskii, Li Ding, D.R. Mani, Steven A. Carr, Alex Webster, Alicia Francis, Alyssa Charamut, Amanda G. Paulovich, Amy M. Perou, Andrew K. Godwin, Andrii Karnuta, Annette Marrero-Oliveras, Barbara Hindenach, Barbara L. Pruetz, Bartosz Kubisa, Brian Druker, Chet Birger, Corbin D. Jones, Dana R. Valley, Daniel C. Rohrer, Daniel Cui Zhou, Daniel W. Chan, David Chesla, David Clark, Dmitry Rykunov, Donghui Tan, Elena V. Ponomareva, Elizabeth R. Duffy, Eric Burks, Eric E. Schadt, Erik J. Bergstrom, Eugene Fedorov, Ewa P. Malc, George D. Wilson, Haiquan Chen, Halina Krzystek
Abstract
To explore the biology of lung adenocarcinoma (LUAD) and identify new therapeutic opportunities, we performed comprehensive proteogenomic characterization of 110 tumors and 101 matched normal adjacent tissues (NATs) incorporating genomics, epigenomics, deep-scale proteomics, phosphoproteomics, and acetylproteomics. Multi-omics clustering revealed four subgroups defined by key driver mutations, country, and gender. Proteomic and phosphoproteomic data illuminated biology downstream of copy number aberrations, somatic mutations, and fusions and identified therapeutic vulnerabilities associated with driver events involving KRAS, EGFR, and ALK. Immune subtyping revealed a complex landscape, reinforced the association of STK11 with immune-cold behavior, and underscored a potential immunosuppressive role of neutrophil degranulation. Smoking-associated LUADs showed correlation with other environmental exposure signatures and a field effect in NATs. Matched NATs allowed identification of differentially expressed proteins with potential diagnostic and therapeutic utility. This proteogenomics dataset represents a unique public resource for researchers and clinicians seeking to better understand and treat lung adenocarcinomas.