title: Synergistic effects of crizotinib and radiotherapy in experimental EML4-ALK fusion positive lung cancer.
abstract: OBJECTIVE
  Non-small cell lung cancer (NSCLC) patients with chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK) are sensitive to the tyrosine kinase inhibitor crizotinib. We aimed to investigate the effects of combined radiotherapy and crizotinib in ALK-positive vs. wild type NSCLC models.
  
  
  METHODS
  Clonogenic survival, proliferation and apoptosis of cells exposed to crizotinib and radiotherapy (photon and carbon ions) were evaluated in ALK mutation positive (ALK+; H3122) and negative (ALK-; A549 and LLC) NSCLC lines. The syngeneic mouse (LLC) and human (H3122) xenograft tumor models were further studied in vivo. Tumor growth kinetics, microvascular density (MVD), perfusion and proliferation were assessed.
  
  
  RESULTS
  Crizotinib exerted potent and selective anti-proliferative and pro-apoptotic effects in ALK+ H3122 cells which were augmented by radiotherapy. The synergistic effect of this combination in ALK+ NSCLC was confirmed by isobologram analysis. Crizotinib also sensitized H3122 cells to particle therapy with carbon ions. In H3122 xenografts, dual combination was most effective in reducing tumor proliferation, MVD and perfusion. In contrast, in the LLC model, crizotinib led only to a transient tumor growth inhibition and combined treatment was inferior to radiotherapy alone.
  
  
  CONCLUSIONS
  Crizotinib elicits beneficial effects in combination with radiotherapy only in ALK-positive NSCLC.
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Germany.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dai
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Germany.
authors.forename: Quanxiang
authors.initials: Q
authors.lastname: Wei
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schwager
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Germany; Department of Clinical Pathology, Suez Canal University, Ismailia, Egypt.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Moustafa
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Germany.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhou
authors.affiliation: FibroGen, Inc., San Francisco, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Pathology, University of Heidelberg Medical School, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Germany. Electronic address: a.amir@dkfz.de.
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D000077547:Crizotinib; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib
keywords: ALK; Crizotinib; Non-small cell lung cancer; Radiotherapy