title: Amplification of CRKL induces transformation and epidermal growth factor receptor inhibitor resistance in human non-small cell lung cancers.
abstract: We previously identified a region of recurrent amplification on chromosome 22q11.21 in a subset of primary lung adenocarcinomas. Here we show that CRKL, encoding for an adaptor protein, is amplified and overexpressed in non-small cell lung cancer (NSCLC) cells that harbor 22q11.21 amplifications. Overexpression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death. Overexpression of CRKL in epidermal growth factor receptor (EGFR)-mutant cells induces resistance to gefitinib by activating extracellular signal-regulated kinase and AKT signaling. We identified CRKL amplification in an EGFR inhibitor-treated lung adenocarcinoma that was not present before treatment. These observations demonstrate that CRKL overexpression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications, and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.
  
  
  CONCLUSIONS
  These studies credential CRKL as an oncogene in a subset of NSCLC. Overexpression of CRKL induces cell transformation and resistance to epidermal growth factor receptor inhibitor treatment and suggest that therapeutic interventions targeting CRKL may confer a clinical benefit in a defined subset of NSCLCs.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
authors.forename: Hihu Wing
authors.initials: HW
authors.lastname: Cheung
authors.forename: Jinyan
authors.initials: J
authors.lastname: Du
authors.forename: Jesse S
authors.initials: JS
authors.lastname: Boehm
authors.forename: Frank
authors.initials: F
authors.lastname: He
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Weir
authors.forename: Xiaoxing
authors.initials: X
authors.lastname: Wang
authors.forename: Mohit
authors.initials: M
authors.lastname: Butaney
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: Biao
authors.initials: B
authors.lastname: Luo
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: David E
authors.initials: DE
authors.lastname: Root
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000077192:Adenocarcinoma of Lung; D016923:Cell Death / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002892:Chromosomes, Human, Pair 22; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009154:Mutation; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D020837:SOS1 Protein / Q000235:genetics / Q000378:metabolism; D000089804:Shelterin Complex; D015398:Signal Transduction; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D025542:Neurofibromin 1; D009687:Nuclear Proteins; D011799:Quinazolines; D020837:SOS1 Protein; D000089804:Shelterin Complex; C440809:TERF2IP protein, human; D034501:Telomere-Binding Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras); D000077156:Gefitinib