21PUveal melanoma cell lines depend on multiple signaling pathways for survival

Abstract Background Uveal melanoma (UM) is a rare cancer that arises from melanocytes in the uveal tract of the eye. Despite effective treatment for primary UM, > 50% of patients develop metastatic disease. There is currently no effective treatment for metastatic UM and median life expectancy is  Methods The response 11 UM cell lines to 6 selective inhibitors was investigated using cell viability assays and cell cycle analyses by flow cytometry. Inhibition of selected pathways was examined using Western analysis of downstream effector proteins. The inhibitors used in this study included PKC inhibitors (AEB071 and LXS196), MEK inhibitor (trametinib), PI3K/mTOR inhibitor (BEZ235), YAP inhibitor (verteporfin) and ARF6 inhibitor (NAV2729). Results PKC inhibitors were most effective with 8 GNAQ/11 mutant UM cell lines showing some degree of sensitivity to each of the inhibitors, although sensitivity was usually associated with proliferative arrest rather than cell death. (see Table) Expression levels of pMARCKS and pERK were strongly inhibited by PKC inhibitors, however inhibition of these effector proteins did not reflect the degree of UM cell sensitivity. Conclusions The sensitivity of GNAQ/11 mutation UM cell lines to 6 targeted drugs is heterogeneous and no single dominant signalling pathway was identified. This suggest that multiple, independent signal pathways contribute to the survival of UM. Thus, inhibition of any single pathway is unlikely to be effective in the treatment of majority of metastatic UM. Table . 21P Summary of UM cell lines to each inhibitor. Combined result of cell viability assay and cell cycle analysis Cell Line Mutation Trametinib BEZ235 NAV2729 AEB071 Verteporfin LXS196 Mel270 GNAQ sensitive sensitive sensitive sensitive sensitive sensitive OMM1 GNA11 resistant sensitive intermediate sensitivity sensitive sensitive sensitive 92.1 GNAQ resistant intermediate sensitivity sensitive intermediate sensitivity sensitive intermediate sensitivity Mel202 GNAQ resistant intermediate sensitivity sensitive intermediate sensitivity sensitive intermediate sensitivity OMM1.3 GNAQ resistant intermediate sensitivity resistant intermediate sensitivity resistant intermediate sensitivity OMM1.5 GNAQ resistant resistant resistant intermediate sensitivity resistant intermediate sensitivity MP41 GNA11 resistant resistant resistant intermediate sensitivity resistant intermediate sensitivity MP46 GNAQ resistant resistant resistant resistant resistant intermediate sensitivity MP38 GNAQ resistant resistant resistant resistant resistant resistant Mel290 Nil resistant intermediate sensitivity resistant resistant resistant resistant Mel285 Nil resistant resistant resistant resistant resistant resistant Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.