title: An Integrated Molecular Analysis of Lung Adenocarcinomas Identifies Potential Therapeutic Targets among TTF1-Negative Tumors, Including DNA Repair Proteins and Nrf2.
abstract: OBJECTIVE
  Thyroid transcription factor-1 (TTF1) immunohistochemistry (IHC) is used clinically to differentiate primary lung adenocarcinomas (LUAD) from squamous lung cancers and metastatic adenocarcinomas from other primary sites. However, a subset of LUAD (15%-20%) does not express TTF1, and TTF1-negative patients have worse clinical outcomes. As there are no established targeted agents with activity in TTF1-negative LUAD, we performed an integrated molecular analysis to identify potential therapeutic targets.
  
  
  METHODS
  Using two clinical LUAD cohorts (274 tumors), one from our institution (PROSPECT) and The Cancer Genome Atlas, we interrogated proteomic profiles (by reverse phase protein array, RPPA), gene expression, and mutational data. Drug response data from 74 cell lines were used to validate potential therapeutic agents.
  
  
  RESULTS
  Strong correlations were observed between TTF1 IHC and TTF1 measurements by RPPA (Rho = 0.57, P < 0.001) and gene expression (NKX2-1, Rho = 0.61, P < 0.001). Established driver mutations (e.g., BRAF and EGFR) were associated with high TTF1 expression. In contrast, TTF1-negative LUAD had a higher frequency of inactivating KEAP1 mutations (P = 0.001). Proteomic profiling identified increased expression of DNA repair proteins (e.g., Chk1 and the DNA repair score) and suppressed PI3k/mTOR signaling among TTF1-negative tumors, with differences in total proteins confirmed at the mRNA level. Cell line analysis showed drugs targeting DNA repair to be more active in TTF1-low cell lines.
  
  
  CONCLUSIONS
  Combined genomic and proteomic analyses demonstrated infrequent alteration of validated lung cancer targets (including the absence of BRAF mutations in TTF1-negative LUAD), but identified novel potential targets for TTF1-negative LUAD, including KEAP1/Nrf2 and DNA repair pathways.
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Robert J G
authors: RJ
authors: Cardnell
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Carmen
authors: C
authors: Behrens
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Lixia
authors: L
authors: Diao
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: YouHong
authors: Y
authors: Fan
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Ximing
authors: X
authors: Tang
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Pan
authors: P
authors: Tong
authors: Hamon Center for Therapeutic Oncology Research and the Simmons Comprehensive Cancer Center, The University of Texas Southwestern, Dallas, Texas.
authors: John D
authors: JD
authors: Minna
authors: Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Gordon B
authors: GB
authors: Mills
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: John V
authors: JV
authors: Heymach
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Ignacio I
authors: II
authors: Wistuba
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Jing
authors: J
authors: Wang
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. lbyers@mdanderson.org.
authors: Lauren A
authors: LA
authors: Byers
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D058990:Molecular Targeted Therapy; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis* / Q000235:genetics; D040901:Proteomics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C504003:TTF1 protein, human; D014157:Transcription Factors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf