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C‐Met signaling and preclinical analysis of Crizotinib in uveal melanoma
Author(s) -
VAN DER VELDEN PA,
DE LANGE M,
DA SILVA CG,
VERSLUIS M,
LUYTEN GPM,
JAGER MJ
Publication year - 2011
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.1755-3768.2011.3363.x
Subject(s) - crizotinib , cancer research , melanoma , metastasis , medicine , kinase , pathology , biology , lung cancer , cancer , microbiology and biotechnology , malignant pleural effusion
Purpose Uveal melanoma (UM) is the most common intra‐ocular tumor in adults that often leads to metastases for which no effective treatment is available. The aim of this study was to analyze molecular mechanisms in UM in order to reveal treatment targets. Methods Efficacy of kinase inhibitors and molecular mechanisms are analyzed in preclinical models of UM. Focus in this study was on the kinases and pathways that are associated with metastasis. Results Based on c‐Met expression in UM with a bad prognosis (monosomy 3) and activation of c‐Met in all metastasis cell lines c‐Met was chosen as treatment target and Crizotinib was chosen as candidate drug. Crizotinib is a dual kinase inhibitor that inhibits both ALK and c‐Met. Molecular analysis revealed that Crizotinib was able to inhibit c‐Met in UM effectively at nano‐molar range. Proliferation was however not affected by Crizotinib treatment when cells were grown attached to culture dishes. To achieve growth inhibition with Crizotinib cells had to be grown non‐attached. Moreover, only tumor cells that contained activated c‐Met were affected by Crizotinib while c‐Met negative cells continued to grow in the presence of the drug. Molecular analysis furthermore revealed that focal adhesion kinase (FAK) is a downstream target that was also inactivated in response to Crizotinib treatment. FAK is involved in tumor cell motility and tumor cell extravasation that are both crucial processes in metastasis. Conclusion We propose Crizotinib as a possible treatment option for metastasizing UM. As c‐Met expression is highly correlated with monosomy 3, both c‐Met and monosomy 3 may be evaluated as biomarker for Crizotinib treatment.