title: Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. lbyers@mdanderson.org
authors.forename: Lauren Averett
authors.initials: LA
authors.lastname: Byers
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Monique B
authors.initials: MB
authors.lastname: Nilsson
authors.forename: Junya
authors.initials: J
authors.lastname: Fujimoto
authors.forename: Pierre
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authors.lastname: Saintigny
authors.forename: John
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authors.lastname: Yordy
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authors.lastname: Giri
authors.forename: Michael
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authors.lastname: Peyton
authors.forename: You Hong
authors.initials: YH
authors.lastname: Fan
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Masrorpour
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Wenbin
authors.initials: W
authors.lastname: Liu
authors.forename: Boris
authors.initials: B
authors.lastname: Duchemann
authors.forename: Praveen
authors.initials: P
authors.lastname: Tumula
authors.forename: Vikas
authors.initials: V
authors.lastname: Bhardwaj
authors.forename: James
authors.initials: J
authors.lastname: Welsh
authors.forename: Stephanie
authors.initials: S
authors.lastname: Weber
authors.forename: Bonnie S
authors.initials: BS
authors.lastname: Glisson
authors.forename: Neda
authors.initials: N
authors.lastname: Kalhor
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020543:Proteome / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051135:Rad51 Recombinase / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D007211:Indoles; D019869:Phosphatidylinositol 3-Kinases; D010793:Phthalazines; D010879:Piperazines; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; D020543:Proteome; D012333:RNA, Messenger; D051135:Rad51 Recombinase; D020794:Receptor Protein-Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C531549:rucaparib; C499320:PARP1 protein, human; C546842:MTOR protein, human; C495153:RAD51 protein, human; C531550:olaparib