An integrated molecular analysis of lung adenocarcinomas identifies potential therapeutic targets among TTF1-negative tumors, including DNA Repair Proteins and Nrf2

Robert J.G. Cardnell, Carmen Behrens, Lixia Diao, You Hong Fan, Ximing Tang, Pan Tong, John D. Minna, Gordon Mills, John V. Heymach, Ignacio I. Wistuba, Jing Wang, Lauren A. Byers

Research output: Contribution to journalArticle

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Abstract

Purpose: 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. Experimental Design: 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), geneexpression, 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.

Original languageEnglish (US)
Pages (from-to)3480-3491
Number of pages12
JournalClinical Cancer Research
Volume21
Issue number15
DOIs
StatePublished - Aug 1 2015
Externally publishedYes

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DNA Repair
Neoplasms
Proteins
Therapeutics
Proteomics
Protein Array Analysis
Cell Line
Mutation
Adenocarcinoma of lung
thyroid nuclear factor 1
Lung Neoplasms
Immunohistochemistry
Atlases
Drug Delivery Systems
Adenocarcinoma
Research Design
Genome
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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An integrated molecular analysis of lung adenocarcinomas identifies potential therapeutic targets among TTF1-negative tumors, including DNA Repair Proteins and Nrf2. / Cardnell, Robert J.G.; Behrens, Carmen; Diao, Lixia; Fan, You Hong; Tang, Ximing; Tong, Pan; Minna, John D.; Mills, Gordon; Heymach, John V.; Wistuba, Ignacio I.; Wang, Jing; Byers, Lauren A.

In: Clinical Cancer Research, Vol. 21, No. 15, 01.08.2015, p. 3480-3491.

Research output: Contribution to journalArticle

Cardnell, RJG, Behrens, C, Diao, L, Fan, YH, Tang, X, Tong, P, Minna, JD, Mills, G, Heymach, JV, Wistuba, II, Wang, J & Byers, LA 2015, 'An integrated molecular analysis of lung adenocarcinomas identifies potential therapeutic targets among TTF1-negative tumors, including DNA Repair Proteins and Nrf2', Clinical Cancer Research, vol. 21, no. 15, pp. 3480-3491. https://doi.org/10.1158/1078-0432.CCR-14-3286
Cardnell, Robert J.G. ; Behrens, Carmen ; Diao, Lixia ; Fan, You Hong ; Tang, Ximing ; Tong, Pan ; Minna, John D. ; Mills, Gordon ; Heymach, John V. ; Wistuba, Ignacio I. ; Wang, Jing ; Byers, Lauren A. / An integrated molecular analysis of lung adenocarcinomas identifies potential therapeutic targets among TTF1-negative tumors, including DNA Repair Proteins and Nrf2. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 15. pp. 3480-3491.
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abstract = "Purpose: 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. Experimental Design: 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), geneexpression, 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.",
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AU - Cardnell, Robert J.G.

AU - Behrens, Carmen

AU - Diao, Lixia

AU - Fan, You Hong

AU - Tang, Ximing

AU - Tong, Pan

AU - Minna, John D.

AU - Mills, Gordon

AU - Heymach, John V.

AU - Wistuba, Ignacio I.

AU - Wang, Jing

AU - Byers, Lauren A.

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N2 - Purpose: 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. Experimental Design: 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), geneexpression, 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.

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