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Abstract：
Uveal Melanoma (UM) is a rare and malignant intraocular tumor with dismal prognosis. Even if radiation or surgery permit an efficient control of the primary tumor, up to 50% of patients subsequently develop metastases, mainly in the liver. The treatment of UM metastases is challenging and the patient survival is very poor. The most recurrent event in UM is the activation of Gαq signaling induced by mutations in GNAQ/11. These mutations activate downstream effectors including protein kinase C (PKC) and mitogen-activated protein kinases (MAPK). Clinical trials with inhibitors of these targets have not demonstrated a survival benefit for patients with UM metastasis. Recently, it has been shown that GNAQ promotes YAP activation through the focal adhesion kinase (FAK). Pharmacological inhibition of MEK and FAK showed remarkable synergistic growth-inhibitory effects in UM both in vitro and in vivo. In this study, we have evaluated the synergy of the FAK inhibitor with a series of inhibitors targeting recognized UM deregulated pathways in a panel of cell lines. The combined inhibition of FAK and MEK or PKC had highly synergistic effects by reducing cell viability and inducing apoptosis. Furthermore, we demonstrated that these combinations exert a remarkable in vivo activity in UM patient-derived xenografts. Our study confirms the previously described synergy of the dual inhibition of FAK and MEK and identifies a novel combination of drugs (FAK and PKC inhibitors) as a promising strategy for therapeutic intervention in metastatic UM.
摘要：
葡萄膜黑色素瘤（UM）是一种罕见的恶性眼内肿瘤，预后不良。即使放疗或手术可以有效控制原发肿瘤，高达50%的患者随后发生转移，主要在肝脏。UM转移的治疗是具有挑战性的,并且患者的存活率非常差。UM中最反复出现的事件是GNAQ/11突变诱导的Gαq信号激活。这些突变激活下游效应物,包括蛋白激酶C(PKC)和丝裂原活化蛋白激酶(MAPK)。使用这些靶标的抑制剂的临床试验尚未证明对患有UM转移的患者的生存益处。最近,已经显示GNAQ通过粘着斑激酶(FAK)促进YAP活化。MEK和FAK的药理学抑制在体外和体内均在UM中显示出明显的协同生长抑制作用。在这项研究中,我们评估了FAK抑制剂与一系列针对一组细胞系中公认的UM失调途径的抑制剂的协同作用.FAK和MEK或PKC的联合抑制通过降低细胞活力和诱导细胞凋亡而具有高度协同作用。此外，我们证明了这些组合在UM患者来源的异种移植物中具有显着的体内活性。我们的研究证实了先前描述的FAK和MEK双重抑制的协同作用，并确定了一种新型药物组合（FAK和PKC抑制剂）作为转移性UM治疗干预的有希望的策略。
