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Pieter van der Velden, Mark de Lange, Mieke Versluis, Gregorius Luyten, Martine Jager, Leiden uveal melanoma group; Pre-clinical analysis of Crizotinib in MAPK independent uveal melanoma metastases. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4207.
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© ARVO (1962-2015); The Authors (2016-present)
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. Metastases 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 therapy.
We used antibody arrays to identify the pathways that are activated in UM metastases and based on this analysis, kinase inhibitors were selected to treat UM. Treated UM cells were in vitro characterized for metastatic potential with anchorage independent colony formation and migration assays using soft agar and 3D sphere assays.
In MAPK independent UM metastases constitutive c-Met activation was observed. Malignant UM displayed MAPK activation as well as c-Met activation. Treatment with Crizotinib reduced c-Met activation and this resulted in reduced growth that was aggravated in anchorage independent cell cultures. UM cells with activated c-Met that were captured in 3D spheres revealed a reduced capacity to migrate upon Crizotinib treatment compared to cells that lack activated c-Met.
In malignant UM and UM metastases c-Met activation was observed and Crizotinib was selected as a potential treatment option. Growth inhibition by Crizotinib occurred by MAPK dependent and MAPK independent mechanisms while inhibition of migration was correlated with c-Met status. Combined our data revealed c-Met signalling in progression of UM and support the use of Crizotinib for malignant and metastatic UM treatment.
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