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ALK inhibitor PF02341066 (crizotinib) increases sensitivity to radiation in non-small cell lung cancer expressing EML4-ALK. Mol Cancer Ther 2013 May;12(5):696-704

Date

02/28/2013

Pubmed ID

23443800

Pubmed Central ID

PMC3651772

DOI

10.1158/1535-7163.MCT-12-0868

Abstract

Crizotinib (PF02341066) is a tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) that has been shown to selectively inhibit growth of cancer cells that harbor the EML4-ALK fusion found in a subset of patients with non-small cell lung cancer (NSCLC). While in clinical trials, PF02341066 has shown a significant therapeutic benefit as a single agent; the effectiveness of combining it with other therapeutic modalities including ionizing radiation remains unknown. To further elucidate the role of PF02341066 in tumor inhibition, we examined its effects alone and in combination with radiation on downstream signaling, apoptosis, and radiosensitivity in two NSCLC cell lines in vitro: H3122, which harbors the EML4-ALK fusion, and H460, which does not. We also examined the in vivo effects of PF02341066 in H3122 mouse xenografts. In the H3122 cell line, PF02341066 inhibited phosphorylation of ALK and its downstream effectors: AKT, ERK, and STAT3. H3122 cells treated with a combination of PF02341066 and radiation showed an increase in cellular apoptosis and were sensitized to radiation therapy (dose enhancement ratio, 1.43; P < 0.0001). Moreover, in an H3122 xenograft model, the combined treatment resulted in greater tumor growth inhibition than either treatment alone (P < 0.05). None of these effects was observed in the EML4-ALK-negative H460 cells. Our findings indicate that PF02341066 acts as a radiation sensitizer in cells harboring the EML4-ALK fusion, providing a rationale for a clinical trial combining ALK inhibitor with radiation in the NSCLCs expressing ALK.

Author List

Sun Y, Nowak KA, Zaorsky NG, Winchester CL, Dalal K, Giacalone NJ, Liu N, Werner-Wasik M, Wasik MA, Dicker AP, Lu B

Author

Yunguang Sun MD, PhD Assistant Professor in the Pathology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Carcinoma, Non-Small-Cell Lung
Cell Line, Tumor
Cell Proliferation
Dose-Response Relationship, Drug
Female
Gene Expression Regulation
Humans
Lung Neoplasms
Mice
Oncogene Proteins, Fusion
Phosphorylation
Protein Kinase Inhibitors
Pyrazoles
Pyridines
Radiation Tolerance
Receptor Protein-Tyrosine Kinases
Signal Transduction
Tumor Burden
Xenograft Model Antitumor Assays
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a