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 & 8 others Ignacio I. Wistuba, Luc Girard, Scott M. Lippman, Gordon B. Mills, Kevin R. Coombes, John N. Weinstein, John D. Minna, John V. Heymach

Research output: Contribution to journalArticle

208 Citations (Scopus)

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 profi led 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.

Original languageEnglish (US)
Pages (from-to)798-811
Number of pages14
JournalCancer Discovery
Volume2
Issue number9
DOIs
StatePublished - Sep 2012

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Small Cell Lung Carcinoma
Proteomics
DNA Repair
Proteins
MAP Kinase Kinase Kinases
Drug Therapy
Thymidylate Synthase
1-Phosphatidylinositol 4-Kinase
Extracellular Signal-Regulated MAP Kinases
Receptor Protein-Tyrosine Kinases
Therapeutics
Mitogens
Non-Small Cell Lung Carcinoma
Neoplasms
Down-Regulation
Survival Rate
Apoptosis
Messenger RNA
Survival
Enhancer of Zeste Homolog 2 Protein

ASJC Scopus subject areas

  • Oncology

Cite this

Byers, L. A., Wang, J., Nilsson, M. B., Fujimoto, J., Saintigny, P., Yordy, J., ... Heymach, J. V. (2012). Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. Cancer Discovery, 2(9), 798-811. https://doi.org/10.1158/2159-8290.CD-12-0112

Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. / Byers, Lauren Averett; Wang, Jing; Nilsson, Monique B.; Fujimoto, Junya; Saintigny, Pierre; Yordy, John; Giri, Uma; Peyton, Michael; Fan, You Hong; Diao, Lixia; Masrorpour, Fatemeh; Shen, Li; Liu, Wenbin; Duchemann, Boris; Tumula, Praveen; Bhardwaj, Vikas; Welsh, James; Weber, Stephanie; Glisson, Bonnie S.; Kalhor, Neda; Wistuba, Ignacio I.; Girard, Luc; Lippman, Scott M.; Mills, Gordon B.; Coombes, Kevin R.; Weinstein, John N.; Minna, John D.; Heymach, John V.

In: Cancer Discovery, Vol. 2, No. 9, 09.2012, p. 798-811.

Research output: Contribution to journalArticle

Byers, LA, Wang, J, Nilsson, MB, Fujimoto, J, Saintigny, P, Yordy, J, Giri, U, Peyton, M, Fan, YH, Diao, L, Masrorpour, F, Shen, L, Liu, W, Duchemann, B, Tumula, P, Bhardwaj, V, Welsh, J, Weber, S, Glisson, BS, Kalhor, N, Wistuba, II, Girard, L, Lippman, SM, Mills, GB, Coombes, KR, Weinstein, JN, Minna, JD & Heymach, JV 2012, 'Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1', Cancer Discovery, vol. 2, no. 9, pp. 798-811. https://doi.org/10.1158/2159-8290.CD-12-0112
Byers, Lauren Averett ; Wang, Jing ; Nilsson, Monique B. ; Fujimoto, Junya ; Saintigny, Pierre ; Yordy, John ; Giri, Uma ; Peyton, Michael ; Fan, You Hong ; Diao, Lixia ; Masrorpour, Fatemeh ; Shen, Li ; Liu, Wenbin ; Duchemann, Boris ; Tumula, Praveen ; Bhardwaj, Vikas ; Welsh, James ; Weber, Stephanie ; Glisson, Bonnie S. ; Kalhor, Neda ; Wistuba, Ignacio I. ; Girard, Luc ; Lippman, Scott M. ; Mills, Gordon B. ; Coombes, Kevin R. ; Weinstein, John N. ; Minna, John D. ; Heymach, John V. / Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1. In: Cancer Discovery. 2012 ; Vol. 2, No. 9. pp. 798-811.
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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 profi led 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.",
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AU - Saintigny, Pierre

AU - Yordy, John

AU - Giri, Uma

AU - Peyton, Michael

AU - Fan, You Hong

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AU - Lippman, Scott M.

AU - Mills, Gordon B.

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