Synergistic effects of crizotinib and radiotherapy in experimental EML4-ALK fusion positive lung cancer.

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.

• Authors: Ying Dai, Quanxiang Wei, Christian Schwager, Mahmoud Moustafa, Cheng Zhou, Kenneth E Lipson, Wilko Weichert, Jürgen Debus, Amir Abdollahi
• Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology (Radiother Oncol) Vol. 114 Issue 2 Pg. 173-81 (Feb 2015) ISSN: 1879-0887 [Electronic] Ireland
• PMID: 25592111 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• EML4-ALK fusion protein, human
• Oncogene Proteins, Fusion
• Protein Kinase Inhibitors
• Pyrazoles
• Pyridines
• Crizotinib

Topics

• Animals
• Apoptosis (drug effects, radiation effects)
• Carcinoma, Lewis Lung (drug therapy, metabolism, pathology, radiotherapy)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, pathology, radiotherapy)
• Cell Line, Tumor
• Chemoradiotherapy
• Crizotinib
• Drug Synergism
• Female
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology, radiotherapy)
• Mice
• Mice, Inbred C57BL
• Oncogene Proteins, Fusion (biosynthesis, genetics)
• Protein Kinase Inhibitors (pharmacology)
• Pyrazoles (pharmacology)
• Pyridines (pharmacology)
• Random Allocation
• Xenograft Model Antitumor Assays