title: Crizotinib-Resistant ROS1 Mutations Reveal a Predictive Kinase Inhibitor Sensitivity Model for ROS1- and ALK-Rearranged Lung Cancers.
abstract: BACKGROUND
  The identification of molecular mechanisms conferring resistance to tyrosine kinase inhibitor (TKI) is a key step to improve therapeutic results for patients with oncogene addiction. Several alterations leading to EGFR and anaplastic lymphoma kinase (ALK) resistance to TKI therapy have been described in non-small cell lung cancer (NSCLC). Only two mutations in the ROS1 kinase domain responsible for crizotinib resistance have been described in patients thus far.
  
  
  METHODS
  A patient suffering from a metastatic NSCLC harboring an ezrin (EZR)-ROS1 fusion gene developed acquired resistance to the ALK/ROS1 inhibitor crizotinib. Molecular analysis (whole-exome sequencing, CGH) and functional studies were undertaken to elucidate the mechanism of resistance. Based on this case, we took advantage of the structural homology of ROS1 and ALK to build a predictive model for drug sensitivity regarding future ROS1 mutations.
  
  
  RESULTS
  Sequencing revealed a dual mutation, S1986Y and S1986F, in the ROS1 kinase domain. Functional in vitro studies demonstrated that ROS1 harboring either the S1986Y or the S1986F mutation, while conferring resistance to crizotinib and ceritinib, was inhibited by lorlatinib (PF-06463922). The patient's clinical response confirmed the potency of lorlatinib against S1986Y/F mutations. The ROS1 S1986Y/F and ALK C1156Y mutations are homologous and displayed similar sensitivity patterns to ALK/ROS1 TKIs. We extended this analogy to build a model predicting TKI efficacy against potential ROS1 mutations.
  
  
  CONCLUSIONS
  Clinical evidence, in vitro validation, and homology-based prediction provide guidance for treatment decision making for patients with ROS1-rearranged NSCLC who progressed on crizotinib. Clin Cancer Res; 22(24); 5983-91. ©2016 AACR.
authors.affiliation: INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France.
authors.forename: Francesco
authors.initials: F
authors.lastname: Facchinetti
authors.affiliation: INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France.|Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Loriot
authors.affiliation: INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France.
authors.forename: Mei-Shiue
authors.initials: MS
authors.lastname: Kuo
authors.affiliation: Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Linda
authors.initials: L
authors.lastname: Mahjoubi
authors.affiliation: INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France.|Translational Research Laboratory and BioBank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Villejuif, France.|Department of Pathology and Laboratory Medicine (BIOpath), Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: David
authors.initials: D
authors.lastname: Planchard
authors.affiliation: Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.|Université Paris Saclay, Université Paris Sud, Faculté de médecine de Bicêtre, Kremlin-Bicêtre, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Besse
authors.affiliation: INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France.|Translational Research Laboratory and BioBank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Farace
authors.affiliation: Department of Pathology and Laboratory Medicine (BIOpath), Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Auger
authors.affiliation: Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.
authors.forename: Jordi
authors.initials: J
authors.lastname: Remon
authors.affiliation: Translational Research Laboratory and BioBank, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy Cancer Campus, Villejuif, France.|Department of Pathology and Laboratory Medicine (BIOpath), Gustave Roussy Cancer Campus, Villejuif, France.|Université Paris Saclay, Université Paris Sud, Faculté de médecine de Bicêtre, Kremlin-Bicêtre, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France.|Department of Medical Oncology, Gustave Roussy Cancer Campus, Villejuif, France.|Université Paris Saclay, Université Paris Sud, Faculté de médecine de Bicêtre, Kremlin-Bicêtre, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.affiliation: INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France.|Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Villejuif, France.|Université Paris Saclay, Université Paris Sud, Faculté de médecine de Bicêtre, Kremlin-Bicêtre, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: INSERM U981, Gustave Roussy Cancer Campus, Université Paris-Sud, Villejuif, France. luc.friboulet@gustaveroussy.fr.
authors.forename: Luc
authors.initials: L
authors.lastname: Friboulet
mesh_terms: D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007769:Lactams; D047029:Lactams, Macrocyclic / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013450:Sulfones / Q000627:therapeutic use
chemical_list: D000631:Aminopyridines; D007769:Lactams; D047029:Lactams, Macrocyclic; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D011743:Pyrimidines; D013450:Sulfones; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; C062333:ROS1 protein, human; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib; C000590786:lorlatinib