Musi Elgilda, Schwartz Gary K, Yoo Jae Hyuk, Odelberg Shannon J, Li Dean Y, Bonner Michael Y, Selvakumar Ponniah, Rao Shikha, Gilbert Linda C, Elsey Justin, Arbiser Jack L
Department of Medicine, Columbia University Medical Center, New York, New York, USA.
Herbert Irving Comprehensive Cancer Center, Columbia University College of Medicine, New York, New York, USA.
Oncotarget. 2019 Jul 9;10(43):4424-4436. doi: 10.18632/oncotarget.27040.
Uveal melanoma is a rare but often lethal malignancy and is the leading cause of death due to an ophthalmic condition. Uveal melanoma is often diagnosed at a late stage and has a strong propensity to hepatic metastasis. Recently, the most common driver mutations in uveal melanoma have been identified, predominantly in the G-proteins GNAQ. This pattern differs from that of cutaneous melanoma in which Braf and Nras predominate. There are no current clinically used agents that target GNAQ mutations, unlike the use of Braf inhibitors in cutaneous melanoma. We tested the novel agent Tris DBA palladium and found that it was markedly more effective against GNAQ mutant melanomas than wild type uveal melanomas. Given that ARF6 has recently been discovered as a node in GNAQ mutations, we evaluated the efficacy of Tris DBA palladium on ARF6 signaling and found that it was effective in inhibiting ARF6 activation. Finally, Tris DBA palladium was orally effective against GNAQ mutant melanoma . Tris DBA Palladium deserves further evaluation as a systemic agent for uveal melanoma.
葡萄膜黑色素瘤是一种罕见但通常致命的恶性肿瘤，是眼科疾病导致死亡的主要原因。葡萄膜黑色素瘤常被诊断为晚期，并且有很强的肝转移倾向。最近，已确定葡萄膜黑色素瘤中最常见的驱动突变，主要存在于G蛋白GNAQ中。这种模式与皮肤黑色素瘤不同，后者以Braf和Nras为主。与皮肤黑色素瘤中使用Braf抑制剂不同，目前没有针对GNAQ突变的临床使用药物。我们测试了新型药物三（二苄叉丙酮）二钯，发现它对GNAQ突变型黑色素瘤的疗效明显优于野生型葡萄膜黑色素瘤。鉴于ARF6最近被发现是GNAQ突变中的一个节点，我们评估了三（二苄叉丙酮）二钯对ARF6信号传导的疗效，发现它能有效抑制ARF6激活。最后，三（二苄叉丙酮）二钯对GNAQ突变型黑色素瘤口服有效。三（二苄叉丙酮）二钯作为一种治疗葡萄膜黑色素瘤的全身用药值得进一步评估。
