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  • Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma.

Proteogenomic Characterization Reveals Therapeutic Vulnerabilities in Lung Adenocarcinoma.

Cell (2020-07-11)
Michael A Gillette, Shankha Satpathy, Song Cao, Saravana M Dhanasekaran, Suhas V 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 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 B Kothadia, Weiping Ma, Seungyeul Yoo, Rahul Mannan, Pankaj Vats, Chandan Kumar-Sinha, Emily A Kawaler, Tatiana Omelchenko, Antonio Colaprico, Yifat Geffen, Yosef E Maruvka, Felipe da Veiga Leprevost, Maciej Wiznerowicz, Zeynep H Gümüş, Rajwanth R 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 P Cieslik, Ana I Robles, Karl R Clauser, Ramaswamy Govindan, Pei Wang, Alexey I Nesvizhskii, Li Ding, D R Mani, Steven A Carr
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.

MATERIALS
Product Number
Brand
Product Description

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Sodium chloride, BioUltra, for molecular biology, ≥99.5% (AT)
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Pyridinium chlorochromate, 98%
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Phosphatase Inhibitor Cocktail 2, aqueous solution (dark coloration may develop upon storage, which does not affect the activity)
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Nα-Acetyl-L-lysine
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Phosphatase Inhibitor Cocktail 3, DMSO solution
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O-Phospho-L-tyrosine
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Phenylmethanesulfonyl fluoride, ≥99.0% (T)
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Iron(III) chloride, anhydrous, powder, ≥99.99% trace metals basis
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Aprotinin Nicotiana tobacco, >= 5TIU/mg protein, >= 98 % SDS-PAGE | 9087-70-1, recombinant, expressed in Nicotiana (tobacco), ≥5 TIU/mg protein, ≥98% (SDS-PAGE)
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N-[Tris(hydroxymethyl)methyl]acrylamide, contains ≤7% KCl, 93%
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Hydroxylamine solution, 50 wt. % in H2O
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Ethylenediaminetetraacetic acid disodium salt solution, for molecular biology, 0.5 M in H2O, DNase, RNase, NICKase and protease, none detected
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Urea, BioXtra, pH 7.5-9.5 (20 °C, 5 M in H2O)
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Iodoacetamide, Single use vial of 56 mg
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Formic acid, reagent grade, ≥95%
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Sodium fluoride, BioXtra, ≥99%
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Ammonium hydroxide solution, 28% NH3 in H2O, ≥99.99% trace metals basis
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Trifluoroacetic acid, suitable for HPLC, ≥99.0%
BRAND® 96-well microplate, U-bottom, round bottom, non-sterile
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Potassium phosphate dibasic, ACS reagent, ≥98%
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Potassium phosphate monobasic, ACS reagent, ≥99.0%
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Sodium phosphate dibasic, ACS reagent, ≥99.0%