Targeting oncogenic signaling in uveal melanoma

Approximately 50% of patients with uveal melanoma (UM) develop liver metastases, and these patients have poor prognosis with a median overall survival of 10 months. There are currently no effective standard therapies to treat metastatic UM, although recent clinical trials with the novel immunotherapy, tebentafusp, improved the survival of a subset of patients with advanced UM. Molecular therapies are also being investigated in UM, and these therapies target the downstream activated signals induced by gain-of-function mutations in the GNAQ and GNA11 genes. These genes are mutated in 50% and 46% of UM patients, respectively and encode guanine nucleotide Ga subunits which transmit signals, via the protein kinase C (PKC), to multiple proliferative and survival pathways, including the MAPK and PI3K/AKT cascades. We studied the effects of the clinically active PKC inhibitor LXS196, on proliferation, clonogenicity, and survival in four GNAQ/GNA11 mutant UM cell lines. LXS196 was a potent inhibitor of the MAPK and PI3K/AKT pathways and suppressed the proliferation of all UM cell lines tested in this study. The inhibition of PKC, MAPK and PI3K signaling only induced apoptosis in two of the four UM cell lines, however. We explored effectors of resistance to PKC inhibition and confirmed that MAPK reactivation was a potent mechanism of PKC inhibitor resistance in UM. AKT activation diminished, but did not eliminate, UM cell sensitivity to PKC inhibition. This work confirms that PKC signaling activates multiple downstream survival pathways in UM, and thus PKC inhibitor sensitivity can be modified by independent mechanisms that activate these survival networks.