crizotinib and Uveal-Neoplasms

To present a case of uveal metastases in a patient with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer and the response to systemic ALK inhibitors.. A retrospective case report. A 75-year-old nonsmoker who has ALK-positive left upper bronchus adenocarcinoma-developed uveal metastases during his course of treatment.. Initially, the patient's disseminated malignancy showed a significant response to crizotinib. However, because the bone metastases started progressing again and he developed bilateral ocular metastases, he was switched to ceritinib. After initiation of ceritinib therapy, the uveal melanomas have shown a significant decrease in thickness and no new lesions have developed.. ALK inhibitors are an effective first-line treatment in patients with ALK-positive uveal metastases secondary to ALK-positive non-small-cell lung cancer. Despite the fact that crizotinib, a first-generation ALK inhibitor, is initially effective in dealing with non-small-cell lung cancer and its metastases, resistance to it seems to develop on a regular basis. A second-generation ALK inhibitor, such as ceritinib, is also effective in overcoming this resistance in treating those with ALK-positive uveal metastases.

Topics: Adenocarcinoma; Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Male; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Retrospective Studies; Treatment Outcome; Uveal Neoplasms

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.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Crizotinib; Disease Models, Animal; Gene Expression; Gene Knockdown Techniques; Hepatocyte Growth Factor; Humans; Male; Melanoma; Mice; Neoplasm Metastasis; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; RNA, Small Interfering; Tumor Burden; Uveal Neoplasms; Xenograft Model Antitumor Assays