RasGRP3 and Protein Kinase D as therapeutic targets for Uveal Melanoma

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Project summary: Uveal melanoma (UM) accounts for approximately 5% of all melanomas and is the most lethal type of melanoma. 50% of UM patients develop metastasis, mostly to the liver, an invariably lethal complication, which currently cannot be effectively treated. Despite dramatic successes in other melanoma subtypes, immune checkpoint blockade, and targeted therapies have been largely ineffective in metastatic UM and there is an urgent need to identify effective therapies. UM lacks mutations in BRAF, NRAS, NF1 and KIT common in cutaneous melanomas and is genetically defined by mutations in the Gaq signaling pathway. We discovered that RasGRP3, a Ras-guanyl nucleotide exchange factor (RasGEF), is dramatically overexpressed in UM compared to other melanoma subtypes and cancers and links the constitutively activated Gaq pathway to the MAP- kinase pathway. RasGRP3 is also directly activated by oncogenic Gaq signaling via mechanisms that partially depend on PKC. We hypothesize that RasGRP3 is a therapeutic target in UM and seek to understand the mechanism behind its marked upregulation to identify alternative targets for therapy. Our preliminary data implicate protein kinase D (PKD) downstream of PKC to be directly involved in RasGRP3 regulation. Our data also demonstrate that PKD is involved in the adaptive resistance that undermines the efficacy of MEK inhibitors. As a druggable kinase, PKD thus is a possible therapeutic target in UM. In this proposal, we will evaluate both RasGRP3 and PKD as therapeutic targets using newly developed genetically engineered and xenograft models of UM metastatic to the liver and investigate the underlying mechanism of RasGRP3 upregulation in UM (Aim 1 and 2). In Aim 3, we will dissect the mechanism underlying the adaptive resistance to MEK inhibition, which represents a key bottleneck limiting the therapeutic efficacy of MEK inhibition, to identify rational therapy combinations that overcome this resistance and improve the therapeutic efficacy of MEK inhibition in the setting of metastatic UM.