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ERK activation and monosomy 3 are associated with Src expression in uveal melanoma and may serve as biomarkers for Dasatinib treatment
Author(s) -
VERSLUIS M,
EL FILALI M,
BRONKHORST IHG,
BAGHAT A,
LUYTEN GPM,
JAGER MJ,
VAN DER VELDEN PA
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.1755-3768.2011.3362.x
Subject(s) - dasatinib , proto oncogene tyrosine protein kinase src , cancer research , mapk/erk pathway , src family kinase , monosomy , tyrosine kinase , gnaq , medicine , kinase , biology , mutation , microbiology and biotechnology , genetics , chromosome , receptor , gene , karyotype
Purpose Uveal melanoma (UM) leads to metastasis in up to 50% of the patients. Patients at risk are readily identified using an array of prognostic markers but an effective treatment is lacking. We recently identified Src as an important tyrosine kinase that conveys MAPK activation in UM. GNAQ/GNA11 mutations are the common denominators of oncogene signalling in UM and Src is a likely downstream kinase. We describe the preclinical analysis of Dasatinib, a known inhibitor or Src kinase, in UM. Methods Eight tumours were removed, cultured and exposed to Dasatinib treatment. proliferation and MAPK signalling were evaluated. Additionally, 36 UM samples were analyzed for Src/ERK signalling, GNAQ/GNA11 mutation status, chromosome 3 and known histological prognostic parameters. Results Growth arrest was observed in 5 of 8 UM cultures and molecular analysis indicated that Dasatinib inhibited MAPK via Src. Treatment efficacy associated with MAPK and Src kinase activity as UM cells with the highest Src activity and MAPK activation displayed the strongest growth inhibition. Furthermore, treatment responses tended to be better in UM cultures with monosomy 3. In the cohort of primary UM, Src expression was highly correlated with MAPK activation and monosomy 3. Conclusion We identified the Src family kinase inhibitor, Dasatinib, as a treatment option for UM. Dasatinib inhibits UM proliferation and may also inhibit UM progression as an association between Src and monosomy 3 was revealed. Consequently, monosomy 3 analysis in tumour tissue may suffice both the prognosis and choice of treatment.