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Pre‐clinical analysis of Crizotinib in uveal melanoma
Author(s) -
DE LANGE MJ,
VERSLUIS M,
JAGER MJ,
LUYTEN GPM,
VAN DER VELDEN PA
Publication year - 2012
Publication title -
acta ophthalmologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.534
H-Index - 87
eISSN - 1755-3768
pISSN - 1755-375X
DOI - 10.1111/j.1755-3768.2012.3283.x
Subject(s) - crizotinib , mapk/erk pathway , cancer research , melanoma , medicine , kinase , metastasis , chemistry , biology , oncology , cancer , microbiology and biotechnology , lung cancer , malignant pleural effusion
Purpose Uveal melanoma (UM) is an intraocular neoplasm with an annual incidence of 7 per million. UM originates from melanocytes just like cutaneous melanoma (CM) and similar to CM, the MAPK pathway is involved in the development of UM. However, not all UM seem to depend on the activation of this pathway. Loss of ERK signalling may be correlated with progression as the ERK negative cells are derived from UM metastasis. Here, tumours apparently use different mechanisms to proliferate and survive. In this study, we aimed to determine the pathway that is up‐regulated in UM metastases and to inhibit its function with targeted kinase inhibitors. Methods We used pathway profiling to identify the pathways that are important in metastases. Furthermore, the c‐Met inhibitor (Crizotinib) was used to inhibit the c‐Met receptor and to identify downstream targets. Colony formation assays and 3D sphere assays were used to characterize UM cells in a three dimensional environment. Results Reduced c‐Met activation rather than reduced expression was induced with Crizotinib treatment. Subsequently, c‐Met inhibition was correlated with reduced colony formation. c‐Met positive UM cells captured in 3D spheres revealed a reduced capacity to migrate upon Crizotinib treatment compared to cells that lack activated c‐Met. Conclusion c‐Met activation was observed in metastasizing UM where it serves as biomarker for Crizotinib treatment. Efficacy of treatment was shown by inhibition of growth and migration. Combined our data reveals c‐Met signalling in progression of UM and support the use of Crizotinib for UM metastasis.