Ying Dai1, Quanxiang Wei1, Christian Schwager1, Mahmoud Moustafa2, Cheng Zhou1, Kenneth E Lipson3, Wilko Weichert4, Jürgen Debus1, Amir Abdollahi5. 1. German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Germany. 2. 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. 3. FibroGen, Inc., San Francisco, USA. 4. German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Pathology, University of Heidelberg Medical School, Germany. 5. German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Germany. Electronic address: a.amir@dkfz.de.
Abstract
BACKGROUND AND PURPOSE: 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. MATERIAL AND 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.
BACKGROUND AND PURPOSE: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. MATERIAL AND 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: F Couñago; A Rodríguez; P Calvo; J Luna; J L Monroy; B Taboada; V Díaz; N Rodríguez de Dios Journal: Clin Transl Oncol Date: 2016-04-22 Impact factor: 3.405
Authors: Ying Dai; Quanxiang Wei; Christian Schwager; Janina Hanne; Cheng Zhou; Klaus Herfarth; Stefan Rieken; Kenneth E Lipson; Jürgen Debus; Amir Abdollahi Journal: Radiat Oncol Date: 2018-01-05 Impact factor: 3.481
Authors: Claudius Melzig; Azadeh Fahim Golestaneh; Walter Mier; Christian Schwager; Samayita Das; Julian Schlegel; Felix Lasitschka; Hans-Ulrich Kauczor; Jürgen Debus; Uwe Haberkorn; Amir Abdollahi Journal: Oncotarget Date: 2018-07-06