title: ALK mutations conferring differential resistance to structurally diverse ALK inhibitors.
abstract: OBJECTIVE
  EML4-ALK fusions define a subset of lung cancers that can be effectively treated with anaplastic lymphoma kinase (ALK) inhibitors. Unfortunately, the duration of response is heterogeneous and acquired resistance limits their ultimate efficacy. Thus, a better understanding of resistance mechanisms will help to enhance tumor control in EML4-ALK-positive tumors.
  
  
  METHODS
  By applying orthogonal functional mutagenesis screening approaches, we screened for mutations inducing resistance to the aminopyridine PF02341066 (crizotinib) and/or the diaminopyrimidine TAE684.
  
  
  RESULTS
  Here, we show that the resistance mutation, L1196M, as well as other crizotinib resistance mutations (F1174L and G1269S), are highly sensitive to the structurally unrelated ALK inhibitor TAE684. In addition, we identified two novel EML4-ALK resistance mutations (L1198P and D1203N), which unlike previously reported mutations, induced resistance to both ALK inhibitors. An independent resistance screen in ALK-mutant neuroblastoma cells yielded the same L1198P resistance mutation but defined two additional mutations conferring resistance to TAE684 but not to PF02341066.
  
  
  CONCLUSIONS
  Our results show that different ALK resistance mutations as well as different ALK inhibitors impact the therapeutic efficacy in the setting of EML4-ALK fusions and ALK mutations.
authors.affiliation: Max Planck Institute for Neurological Research, Klaus-Joachim-Zülch Laboratories of the Max Planck Society, Köln, Germany.
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Heuckmann
authors.forename: Michael
authors.initials: M
authors.lastname: Hölzel
authors.forename: Martin L
authors.initials: ML
authors.lastname: Sos
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heynck
authors.forename: Hyatt
authors.initials: H
authors.lastname: Balke-Want
authors.forename: Mirjam
authors.initials: M
authors.lastname: Koker
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weiss
authors.forename: Christine M
authors.initials: CM
authors.lastname: Lovly
authors.forename: Christian
authors.initials: C
authors.lastname: Grütter
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
authors.forename: William
authors.initials: W
authors.lastname: Pao
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D012697:Serine Endopeptidases / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; C522504:EML4-ALK fusion protein, human; D008869:Microtubule-Associated Proteins; C516714:NVP-TAE684; D015514:Oncogene Proteins, Fusion; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C415585:EML4 protein, human; D012697:Serine Endopeptidases