Background: NUT carcinoma is a rare aggressive disease caused by BRD4/3-NUT fusion, and C-MYC upregulation plays a key role in the pathogenesis. Here, we report on the clinicopathological characteristics of Korean patients with NUT carcinoma and the in vitro efficacy of MYC-targeting agents against patient-derived NUT carcinoma cell lines.
Materials and methods: Thirteen patients with NUT carcinoma were evaluated for p53, C-MYC, epidermal growth factor receptor (EGFR), HER2, and programmed cell death ligand 1 (PD-L1) by immunohistochemistry. The half maximal inhibitory concentration (IC50) values of NUT carcinoma cell lines (SNU-2972-1, SNU-3178S, HCC2429, and Ty-82) were determined using MYC-targeting agents, including bromodomain and extraterminal (BET) inhibitors (I-BET, OTX-015, AZD5153) and histone deacetylase (HDAC) inhibitors (vorinostat, romidepsin, panobinostat, CUDC-907).
Results: Primary tumor sites included head and neck (n = 9) and lung (n = 4). The patient age ranged from 8 to 73 years with the male/female ratio of 1.2:1. Nine patients died at 3-23.6 months (median, 10.6) after diagnosis. Eight patients had been misdiagnosed initially with other diseases. One patient with metastatic NUT carcinoma who received mass excision plus metastasectomy followed by chemoradiotherapy was a long-term survivor (>27 months). Although expressions of C-MYC (8/12, 73%) and p53 (12/12, 100%) were commonly observed, EGFR, HER2, and PD-L1 expressions were observed in 2 of 7 (29%), 2 of 8 (25%), and 1 of 12 (8.3%) patients, respectively. BET and HDAC inhibitors showed variable but limited in vitro efficacy. However, a dual HDAC/PI3K inhibitor, CUDC-907, was most potent against NUT carcinoma cells, with an IC50 of 5.5-9.0 pmol/L. Consistent with these findings, kinome short interfering RNA screening showed a positive hit for PI3KCA in NUT carcinoma cells. Panobinostat (IC50, 0.4-1.3 nmol/L) and a bivalent BET inhibitor, AZD5153 (IC50, 3.7-8.2 nmol/L), also showed remarkable efficacies.
Conclusion: East Asian patients with NUT carcinoma showed dismal survival outcomes like Western patients, and CUDC-907 might be promising in NUT carcinoma treatment.
Implications for practice: NUT carcinoma (NC) is a disease caused by BRD-NUT fusion leading to C-MYC upregulation. NC is often misdiagnosed and very aggressive, requiring development of effective therapeutic strategy. This article presents the clinicopathological features of the largest series of NCs in East Asians and preclinical sensitivities to MYC-targeting agents in NC cell lines. Patients with NC had grave outcomes and poor response to treatment. Among MYC-targeting agents, including BET and HDAC inhibitors, CUDC-907 (a dual PI3K/HDAC inhibitor) was most effective against NC cells, followed by panobinostat (an HDAC inhibitor) and AZD5153 (a bivalent BET inhibitor). CUDC-907 might be promising in NC treatment.
摘要
背景。NUT 癌是由 BRD4/3‐NUT 基因融合引起的罕见侵袭性疾病，并且 C‐MYC 上调在发病机理中起关键作用。在这里，我们报告了韩国 NUT 癌患者的临床病理特征和 MYC 靶向药物对源于患者的 NUT 癌细胞系的体外功效。
材料和方法。通过免疫组织化学评估 13 名 NUT 癌患者的 p53、C‐MYC、表皮生长因子受体 (EGFR)，HER2 和程序性细胞死亡配体 1 (PD‐L1)。使用 MYC 靶向药物 ‐ 包括溴结构域和末端外 (BET) 抑制剂(I‐BET、OTX‐015、AZD5153)和组蛋白脱乙酰酶 (HDAC) 抑制剂(伏立诺他、罗米地辛、帕比司他、CUDC‐907)‐ 测定 NUT 癌细胞系(SNU‐2972‐1、SNU‐3178S、HCC2429 和 Ty‐82)的半数最大抑制浓度(IC50)值。
结果。肿瘤原发部位包括头颈部(n = 9)和肺部(n = 4)。患者年龄介于 8 至 73 岁之间，男女比例为 1.2:1。确诊后，9 例患者在 3 ‐ 23.6 个月(中位数为 10.6)后死亡。最初有 8 名患者被误诊为其他疾病。一名患有转移性 NUT 癌的患者接受了肿块切除加转移灶切除术，随后进行了放化疗，是一位长期存活患者(> 27 个月)。尽管通常能观察到 C‐MYC(8/12，73%)和 p53(12/12，100%)的表达，但分别在 2 /7 例中(29%)，2/8 例中(25%)以及 1/12 例中(8.3%)观察到 EGFR、HER2 和 PD‐L1 的表达。BET 和 HDAC 抑制剂显示出多样但有限的体外功效。然而，一种 HDAC/PI3K 双靶点抑制剂 ‐ CUDC‐907 ‐ 对 NUT 癌细胞最有效，IC50为 5.5‐9.0 pmol/L。与这些发现一致，激酶组短干扰 RNA 筛查显示 NUT 癌细胞中 PI3KCA 出现阳性结果。帕比司他(IC50， 0.4–1.3 nmol/L)和二价 BET 抑制剂 AZD5153(IC50， 3.7‐8.2 nmol/L)也显示出显著的功效。
结论。患有 NUT 癌的东亚患者表现出与西方患者相似的不乐观的存活结果，而 CUDC‐907 可能在 NUT 癌治疗中颇具前景。
实践意义:NUT 癌 (NC) 是一种由 BRD‐NUT 基因融合引起的C‐MYC 上调的疾病。NC 经常被误诊并且非常具有侵袭性，需要研究出有效的治疗策略。本文介绍了东亚地区最大系列 NC 的临床病理特征以及 NC 细胞系中 MYC 靶向药物的临床前敏感性。NC 患者的结局很严峻，他们对治疗的反应较差。在 MYC 靶向药物中，包括 BET 和 HDAC 抑制剂，CUDC‐907(一种 PI3K/HDAC 双靶点抑制剂)对 NC 细胞最有效，其次是帕比司他(一种 HDAC 抑制剂)和 AZD5153(一种二价 BET 抑制剂)。CUDC‐907 可能在 NC 治疗中颇具前景。
Keywords: BET inhibitor; HDAC inhibitor; MYC‐targeting agents; NUT carcinoma; Treatment outcome.
© AlphaMed Press 2019.