title: Crizotinib, a c-Met inhibitor, prevents metastasis in a metastatic uveal melanoma model.
abstract: Uveal melanoma is the most common primary intraocular malignant tumor in adults and half of the primary tumors will develop fatal metastatic disease to the liver and the lung. Crizotinib, an inhibitor of c-Met, anaplastic lymphoma kinase (ALK), and ROS1, inhibited the phosphorylation of the c-Met receptor but not of ALK or ROS1 in uveal melanoma cells and tumor tissue. Consequently, migration of uveal melanoma cells was suppressed in vitro at a concentration associated with the specific inhibition of c-Met phosphorylation. This effect on cell migration could be recapitulated with siRNA specific to c-Met but not to ALK or ROS1. Therefore, we developed a uveal melanoma metastatic mouse model with EGFP-luciferase-labeled uveal melanoma cells transplanted by retro-orbital injections to test the effect of crizotinib on metastasis. In this model, there was development of melanoma within the eye and also metastases to the liver and lung at 7 weeks after the initial transplantation. When mice were treated with crizotinib starting 1 week after the transplantation, we observed a significant reduction in the development of metastases as compared with untreated control sets. These results indicate that the inhibition of c-Met activity alone may be sufficient to strongly inhibit metastasis of uveal melanoma from forming, suggesting crizotinib as a potential adjuvant therapy for patients with primary uveal melanoma who are at high risk for the development of metastatic disease.
authors.affiliation: Corresponding Author: Gary K. Schwartz, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. schwartg@mskcc.org.
authors.forename: Oliver
authors.initials: O
authors.lastname: Surriga
authors.forename: Vinagolu K
authors.initials: VK
authors.lastname: Rajasekhar
authors.forename: Grazia
authors.initials: G
authors.lastname: Ambrosini
authors.forename: Yildrim
authors.initials: Y
authors.lastname: Dogan
authors.forename: Ruimin
authors.initials: R
authors.lastname: Huang
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D000077547:Crizotinib; D004195:Disease Models, Animal; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014604:Uveal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays; D000098943:Uveal Melanoma
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D000077547:Crizotinib; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met