Protein kinase C (PKC) is activated downstream of gain-of-function GNAQ or GNA11 (GNAQ/GNA11) mutations in over 90% of uveal melanoma (UM). Phase I clinical trials of PKC inhibitors have shown modest response rates with no survival benefit in metastatic UM. Although PKC inhibitors actively suppress mitogen-activated protein kinase (MAPK) signalling in UM, the effect on other UM signalling cascades is not well understood. We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196. Similarly, in GNAQ/GNA11-mutant UM cell models, PKC inhibitor monotherapy effectively suppressed MAPK activity, but PI3K/AKT signalling remained active, and thus, concurrent inhibition of PKC and PI3K/AKT signalling was required to synergistically induce cell death in a panel of GNAQ/GNA11-mutant UM cell lines. We also show that re-activation of MAPK signalling has a dominant role in regulating PKC inhibitor responses in UM and that PI3K/AKT signalling diminishes UM cell sensitivity to PKC inhibitor monotherapy. Thus, combination therapies targeting PKC and PKC-independent signalling nodes, including PI3K/AKT activity, are required to improve responses in patients with metastatic UM.

在超过 90% 的葡萄膜黑色素瘤 (UM) 中，蛋白激酶 C (PKC) 在功能获得性GNAQ或GNA11 ( GNAQ/GNA11 ) 突变的下游被激活。 PKC 抑制剂的 I 期临床试验显示，转移性 UM 的缓解率适中，但没有生存获益。尽管 PKC 抑制剂可主动抑制 UM 中丝裂原激活蛋白激酶 (MAPK) 信号传导，但对其他 UM 信号传导级联的影响尚不清楚。我们检查了 PKC 抑制剂治疗前后收集的 UM 活检组织的转录组，并证实在第二代 PKC 抑制剂 IDE196 治疗期间，MAPK（而非 PI3K/AKT 信号）在早期受到抑制。同样，在 GNAQ/GNA11 突变 UM 细胞模型中，PKC 抑制剂单一疗法有效抑制 MAPK 活性，但 PI3K/AKT 信号传导仍然活跃，因此，需要同时抑制 PKC 和 PI3K/AKT 信号传导才能协同诱导细胞死亡GNAQ/GNA11 突变 UM 细胞系。我们还表明，MAPK 信号传导的重新激活在调节 UM 中 PKC 抑制剂反应中起主导作用，并且 PI3K/AKT 信号传导降低了 UM 细胞对 PKC 抑制剂单一疗法的敏感性。因此，需要针对 PKC 和 PKC 独立信号节点（包括 PI3K/AKT 活性）的联合疗法来改善转移性 UM 患者的反应。