Abstract
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 RAS/RAF/MEK/ERK 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. In these tumours, cells apparently use a different pathway to proliferate and survive. In order to identify treatment targets for metastasis patients we set out to identify the pathway which stimulates proliferation in the ERK negative UM cells. Growth factor receptor screening revealed that activation of c-Met or HGF receptor, is inversely correlated with ERK activation leaving the metastatic UM, halfway progression to metastasis, with both c-Met and ERK activated. In this study, we tested the efficacy of c-Met inhibitor Crizotinib and investigated primary and downstream targets to delineate the role of c-Met signalling in UM progression. Crizotinib was shown to specifically inhibit c-Met positive UM and this was most clear when cells were grown anchorage independent, in line with a role in dissemination for c-Met. With phospho-proteomics we showed that c-Met is the primary target of Crizotinib in UM while FAK emerges as the prime downstream target. Moreover, Src was shown to be the downstream kinase that transmits the c-Met signal to both FAK and ERK in metastatic UM. In UM metastasis, lacking active ERK, Src is absent and FAK is directly activated by c-Met. Combined, our data support the use of Crizotinib in late stage UM and reveals altered c-Met signalling in uveal melanoma progression.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 862. doi:1538-7445.AM2012-862
- ©2012 American Association for Cancer Research