title: An epithelial-mesenchymal transition gene signature predicts resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for overcoming EGFR inhibitor resistance.
abstract: OBJECTIVE
  Epithelial-mesenchymal transition (EMT) has been associated with metastatic spread and EGF receptor (EGFR) inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using non-small cell lung carcinoma (NSCLC) cell lines and patients treated in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study.
  
  
  METHODS
  We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from patients with NSCLC. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE study, and potential therapeutic targets associated with EMT were identified.
  
  
  RESULTS
  Compared with epithelial cells, mesenchymal cells showed significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend toward greater sensitivity to the Axl inhibitor SGI-7079, whereas the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In patients with NSCLC, the EMT signature predicted 8-week disease control in patients receiving erlotinib but not other therapies.
  
  
  CONCLUSIONS
  We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype.
authors.affiliation: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Lauren Averett
authors.initials: LA
authors.lastname: Byers
authors.forename: Lixia
authors.initials: L
authors.lastname: Diao
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Pierre
authors.initials: P
authors.lastname: Saintigny
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: Michael
authors.initials: M
authors.lastname: Peyton
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Youhong
authors.initials: Y
authors.lastname: Fan
authors.forename: Uma
authors.initials: U
authors.lastname: Giri
authors.forename: Praveen K
authors.initials: PK
authors.lastname: Tumula
authors.forename: Monique B
authors.initials: MB
authors.lastname: Nilsson
authors.forename: Jayanthi
authors.initials: J
authors.lastname: Gudikote
authors.forename: Hai
authors.initials: H
authors.lastname: Tran
authors.forename: Robert J G
authors.initials: RJ
authors.lastname: Cardnell
authors.forename: David J
authors.initials: DJ
authors.lastname: Bearss
authors.forename: Steven L
authors.initials: SL
authors.lastname: Warner
authors.forename: Jason M
authors.initials: JM
authors.lastname: Foulks
authors.forename: Steven B
authors.initials: SB
authors.lastname: Kanner
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.forename: Nancy
authors.initials: N
authors.lastname: Krett
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kim
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.forename: George R
authors.initials: GR
authors.lastname: Blumenschein
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: K Kian
authors.initials: KK
authors.lastname: Ang
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Waun K
authors.initials: WK
authors.lastname: Hong
authors.forename: John N
authors.initials: JN
authors.lastname: Weinstein
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Coombes
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020543:Proteome; D040901:Proteomics; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012008:Recurrence; D015203:Reproducibility of Results; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D020543:Proteome; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase