title: Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors.
abstract: OBJECTIVE
  To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686).
  
  
  METHODS
  We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models.
  
  
  RESULTS
  We found recurrent amplification of either MET or ERBB2 in tumors that were resistant or developed resistance to third-generation EGFR inhibitors and show that ERBB2 and MET activation can confer resistance to these compounds. Furthermore, we identified a KRASG12Smutation in a patient with acquired resistance to AZD9291 as a potential driver of acquired resistance. Finally, we show that dual inhibition of EGFR/MEK might be a viable strategy to overcome resistance in EGFR-mutant cells expressing mutant KRAS CONCLUSIONS: Our data suggest that heterogeneous mechanisms of resistance can drive primary and acquired resistance to third-generation EGFR inhibitors and provide a rationale for potential combination strategies. Clin Cancer Res; 22(19); 4837-47. ©2016 AACR.
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Ortiz-Cuaran
authors.affiliation: Department I of Internal Medicine, Lung Cancer Group Cologne and Network Genomic Medicine (Lung Cancer), Center for Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Cologne, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Scheffler
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany. Molecular Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Plenker
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Llona
authors.initials: L
authors.lastname: Dahmen
authors.affiliation: Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Scheel
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany. Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
authors.forename: Lynnette
authors.initials: L
authors.lastname: Fernandez-Cuesta
authors.affiliation: Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Lydia
authors.initials: L
authors.lastname: Meder
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.affiliation: Radiology Department, University Hospital Cologne, Cologne, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Persigehl
authors.affiliation: Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Merkelbach-Bruse
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Bos
authors.affiliation: Department I of Internal Medicine, Lung Cancer Group Cologne and Network Genomic Medicine (Lung Cancer), Center for Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Cologne, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Michels
authors.affiliation: Department I of Internal Medicine, Lung Cancer Group Cologne and Network Genomic Medicine (Lung Cancer), Center for Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Cologne, Germany.
authors.forename: Rieke
authors.initials: R
authors.lastname: Fischer
authors.affiliation: Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Albus
authors.affiliation: Labor Dr. Quade und Kollegen GmbH, Cologne, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: König
authors.affiliation: Institute of Pathology, University Hospital Goettingen, Goettingen, Germany.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schildhaus
authors.affiliation: Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Fassunke
authors.affiliation: Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Michaela A
authors.initials: MA
authors.lastname: Ihle
authors.affiliation: Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany. Pathology of the University Hospital of Luebeck and Leibniz Research Center Borstel, Lübeck and Borstel, Germany.
authors.forename: Helen
authors.initials: H
authors.lastname: Pasternack
authors.affiliation: Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Heydt
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai, China. School of Life Science and Technology, Shanghai Tech University, Shanghai, China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.affiliation: Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Florin
authors.affiliation: NEO New Oncology AG, Cologne, Germany.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Heuckmann
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nuernberg
authors.affiliation: Department I of Internal Medicine, Lung Cancer Group Cologne and Network Genomic Medicine (Lung Cancer), Center for Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Cologne, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Ansén
authors.affiliation: Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany. NEO New Oncology AG, Cologne, Germany.
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authors.initials: LC
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authors.affiliation: Institute for Theoretical Physics. University of Cologne, Cologne, Germany.
authors.forename: Johannes
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authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.affiliation: Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany. martin.sos@uni-koeln.de roman.thomas@uni-koeln.de juergen.wolf@uk-koeln.de reinhard.buettner@uk-koeln.de.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.affiliation: Department I of Internal Medicine, Lung Cancer Group Cologne and Network Genomic Medicine (Lung Cancer), Center for Integrated Oncology Cologne-Bonn, University Hospital Cologne, Cologne, Cologne, Germany. martin.sos@uni-koeln.de roman.thomas@uni-koeln.de juergen.wolf@uk-koeln.de reinhard.buettner@uk-koeln.de.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wolf
authors.affiliation: Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, Cologne, Germany. Institute of Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany. martin.sos@uni-koeln.de roman.thomas@uni-koeln.de juergen.wolf@uk-koeln.de reinhard.buettner@uk-koeln.de.
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
authors.affiliation: Molecular Pathology, Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany. martin.sos@uni-koeln.de roman.thomas@uni-koeln.de juergen.wolf@uk-koeln.de reinhard.buettner@uk-koeln.de.
authors.forename: Martin L
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mesh_terms: D000178:Acrylamides / Q000627:therapeutic use; D000230:Adenocarcinoma / Q000188:drug therapy*; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000814:Aniline Compounds / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000627:therapeutic use; D007211:Indoles
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011743:Pyrimidines; C000596361:osimertinib; D007211:Indoles; C000589977:rociletinib; C512478:EGFR protein, human