Yenisehirli G, Borges S, Braun S, Zuniga A N, Quintana G I, Kutsnetsoff J N, Rodriguez S, Adis E V, Lopez S, Dollar J J, Stathias V, Volmar C H, Karaca E, Brothers S P, Bilbao D C, Harbour J W, Correa Z M, Kurtenbach S
Department of Ophthalmology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine.
Interdisciplinary Stem Cell Institute (ISCI), University of Miami Miller School of Medicine.
bioRxiv. 2025 Feb 25:2024.10.11.617464. doi: 10.1101/2024.10.11.617464.
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with a strong predilection for hepatic metastasis, occurring in approximately 50% of cases. Metastatic UM remains highly resistant to therapy and is almost invariably fatal. The strongest genetic drivers of UM metastasis are loss-of-function mutations in tumor suppressor , an epigenetic regulator that serves as the ubiquitin hydrolase subunit of the polycomb repressive deubiquitinase (PR-DUB) complex, and a key player in global epigenetic regulation. Inactivation of BRCA Associated Protein 1 (BAP1) has been shown to induce widespread epigenetic alterations across multiple model systems. To identify novel therapeutic strategies, we investigated whether targeting the epigenome could reveal new vulnerabilities in UM. We performed high-throughput compound screening using a curated epigenetic inhibitor library and identified BET (bromodomain and extra-terminal domain) inhibition as a particularly promising approach. Interestingly, we observed significant heterogeneity in the efficacy of different BET inhibitors in UM. While previous clinical trials with two BET inhibitors have failed to show efficacy in UM, our findings highlight substantial differences in the potency of specific BET inhibitors for this malignancy. Notably, the BET inhibitor mivebresib (ABBV-075) significantly improved survival rates by 50% in a metastatic UM xenograft mouse model and completely prevented detectable metastases in the bones, spinal cord, and brain. Unexpectedly, RNA sequencing revealed a strong transcriptional overlap between BET inhibition and histone deacetylase (HDAC) inhibition-- an approach currently under clinical evaluation for UM treatment. Both BET and HDAC inhibitors reversed gene expression signatures associated with high metastatic risk and induced a neuronal differentiation-like phenotype in UM cells. Together, our findings demonstrate that UM cells exhibit a distinct vulnerability to BET inhibition and establish BET inhibitors as promising candidates for further clinical evaluation for metastatic UM.
葡萄膜黑色素瘤（UM）是成人中最常见的原发性眼内恶性肿瘤，极易发生肝转移，约50%的病例会出现这种情况。转移性UM对治疗仍具有高度抗性，几乎无一例外都是致命的。UM转移的最强遗传驱动因素是肿瘤抑制因子功能丧失突变，它是一种表观遗传调节剂，作为多梳抑制去泛素化酶（PR-DUB）复合物的泛素水解酶亚基，是全球表观遗传调控的关键参与者。已证明BRCA相关蛋白1（BAP1）失活会在多个模型系统中诱导广泛的表观遗传改变。为了确定新的治疗策略，我们研究了靶向表观基因组是否能揭示UM中的新弱点。我们使用精心策划的表观遗传抑制剂文库进行了高通量化合物筛选，并确定抑制BET（溴结构域和额外末端结构域）是一种特别有前景的方法。有趣的是，我们观察到不同的BET抑制剂在UM中的疗效存在显著异质性。虽然之前使用两种BET抑制剂的临床试验未能在UM中显示出疗效，但我们的研究结果突出了特定BET抑制剂对这种恶性肿瘤的效力存在实质性差异。值得注意的是，BET抑制剂米维布雷西布（ABBV-075）在转移性UM异种移植小鼠模型中显著提高了50%的生存率，并完全预防了骨骼、脊髓和大脑中可检测到的转移。出乎意料的是，RNA测序显示BET抑制和组蛋白脱乙酰酶（HDAC）抑制之间存在强烈的转录重叠——HDAC抑制是目前正在进行UM治疗临床评估的一种方法。BET和HDAC抑制剂都逆转了与高转移风险相关的基因表达特征，并在UM细胞中诱导出类似神经元分化的表型。总之，我们的研究结果表明UM细胞对BET抑制表现出独特的弱点，并将BET抑制剂确立为转移性UM进一步临床评估的有希望的候选药物。
