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Research Articles

Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Lauren Averett Byers, Jing Wang, Monique B. Nilsson, Junya Fujimoto, Pierre Saintigny, John Yordy, Uma Giri, Michael Peyton, You Hong Fan, Lixia Diao, Fatemeh Masrorpour, Li Shen, Wenbin Liu, Boris Duchemann, Praveen Tumula, Vikas Bhardwaj, James Welsh, Stephanie Weber, Bonnie S. Glisson, Neda Kalhor, Ignacio I. Wistuba, Luc Girard, Scott M. Lippman, Gordon B. Mills, Kevin R. Coombes, John N. Weinstein, John D. Minna and John V. Heymach
Lauren Averett Byers
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Jing Wang
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Monique B. Nilsson
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Junya Fujimoto
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Pierre Saintigny
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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John Yordy
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Uma Giri
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Michael Peyton
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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You Hong Fan
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Lixia Diao
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Fatemeh Masrorpour
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Li Shen
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Wenbin Liu
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Boris Duchemann
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Praveen Tumula
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Vikas Bhardwaj
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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James Welsh
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Stephanie Weber
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Bonnie S. Glisson
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Neda Kalhor
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Ignacio I. Wistuba
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Luc Girard
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Scott M. Lippman
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Gordon B. Mills
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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Kevin R. Coombes
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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John N. Weinstein
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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John D. Minna
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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John V. Heymach
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
Departments of 1Thoracic/Head and Neck Medical Oncology, 2Bioinformatics and Computational Biology, 3Pathology, 4Radiation Oncology, 5Systems Biology, and 6Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston; and 7Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern, Dallas, Texas
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DOI: 10.1158/2159-8290.CD-12-0112 Published September 2012
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Abstract

Small cell lung cancer (SCLC) is an aggressive malignancy distinct from non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Using an integrative proteomic and transcriptomic analysis, we investigated molecular differences contributing to the distinct clinical behavior of SCLCs and NSCLCs. SCLCs showed lower levels of several receptor tyrosine kinases and decreased activation of phosphoinositide 3-kinase (PI3K) and Ras/mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) pathways but significantly increased levels of E2F1-regulated factors including enhancer of zeste homolog 2 (EZH2), thymidylate synthase, apoptosis mediators, and DNA repair proteins. In addition, PARP1, a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLCs. SCLC growth was inhibited by PARP1 and EZH2 knockdown. Furthermore, SCLC was significantly more sensitive to PARP inhibitors than were NSCLCs, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy.

Significance: SCLC is a highly lethal cancer with a 5-year survival rate of less than 10%. To date, no molecularly targeted agents have prolonged survival in patients with SCLCs. As a step toward identifying new targets, we systematically profiled SCLCs with a focus on therapeutically relevant signaling pathways. Our data reveal fundamental differences in the patterns of pathway activation in SCLCs and NSCLCs and identify several potential therapeutic targets for SCLCs, including PARP1 and EZH2. On the basis of these results, clinical studies evaluating PARP and EZH2 inhibition, together with chemotherapy or other agents, warrant further investigation. Cancer Discov; 2(9); 798–811. ©2012 AACR.

Read the Commentary on this article by Rosell and Wannesson, p. 769.

This article is highlighted in the In This Issue feature, p. 753.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received March 20, 2012.
  • Revision received June 13, 2012.
  • Accepted June 21, 2012.
  • ©2012 American Association for Cancer Research.
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Cancer Discovery: 2 (9)
September 2012
Volume 2, Issue 9
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Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
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Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Lauren Averett Byers, Jing Wang, Monique B. Nilsson, Junya Fujimoto, Pierre Saintigny, John Yordy, Uma Giri, Michael Peyton, You Hong Fan, Lixia Diao, Fatemeh Masrorpour, Li Shen, Wenbin Liu, Boris Duchemann, Praveen Tumula, Vikas Bhardwaj, James Welsh, Stephanie Weber, Bonnie S. Glisson, Neda Kalhor, Ignacio I. Wistuba, Luc Girard, Scott M. Lippman, Gordon B. Mills, Kevin R. Coombes, John N. Weinstein, John D. Minna and John V. Heymach
Cancer Discov September 1 2012 (2) (9) 798-811; DOI: 10.1158/2159-8290.CD-12-0112

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Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Lauren Averett Byers, Jing Wang, Monique B. Nilsson, Junya Fujimoto, Pierre Saintigny, John Yordy, Uma Giri, Michael Peyton, You Hong Fan, Lixia Diao, Fatemeh Masrorpour, Li Shen, Wenbin Liu, Boris Duchemann, Praveen Tumula, Vikas Bhardwaj, James Welsh, Stephanie Weber, Bonnie S. Glisson, Neda Kalhor, Ignacio I. Wistuba, Luc Girard, Scott M. Lippman, Gordon B. Mills, Kevin R. Coombes, John N. Weinstein, John D. Minna and John V. Heymach
Cancer Discov September 1 2012 (2) (9) 798-811; DOI: 10.1158/2159-8290.CD-12-0112
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