NUT癌是由BRD4/3-NUT融合引起的罕见侵袭性疾病,C-MYC上调在发病机制中起关键作用。这里,我们报道了韩国NUT癌患者的临床病理特征以及MYC靶向药物对患者来源的NUT癌细胞系的体外疗效.
对13例NUT癌患者进行了p53、C-MYC、表皮生长因子受体(EGFR),通过免疫组织化学,HER2和程序性细胞死亡配体1(PD-L1)。NUT癌细胞系的半数最大抑制浓度(IC50)值(SNU-2972-1,SNU-3178S,HCC2429和Ty-82)使用MYC靶向剂确定,包括溴结构域和外端(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,romidepsin,帕比司他,CUDC-907)。
原发肿瘤部位包括头颈部(n=9)和肺部(n=4)。患者年龄为8至73岁,男女比例为1.2:1。9例患者在3-23.6个月死亡(中位数,10.6)诊断后。8例患者最初被误诊为其他疾病。1例转移性NUT癌患者接受肿块切除术加转移瘤切除术后放化疗是长期幸存者(>27个月)。尽管C-MYC(8/12,73%)和p53(12/12,100%)表达普遍,EGFR,HER2和PD-L1表达在7个中的2个(29%)中观察到,8人中的2人(25%),12名患者中有1名(8.3%),分别。BET和HDAC抑制剂显示出可变但有限的体外功效。然而,双重HDAC/PI3K抑制剂,CUDC-907对NUT癌细胞最有效,IC50为5.5-9.0pmol/L与这些发现一致,kinome短干扰RNA筛查显示在NUT癌细胞中PI3KCA阳性。帕比司他(IC50,0.4-1.3nmol/L)和二价BET抑制剂,AZD5153(IC50,3.7-8.2nmol/L),也显示出显着的功效。
与西方患者一样,东亚NUT癌患者的生存结果令人沮丧,和CUDC-907可能在NUT癌治疗中很有前途。
NUT癌(NC)是由BRD-NUT融合引起的导致C-MYC上调的疾病。NC经常被误诊并且非常积极,需要制定有效的治疗策略。本文介绍了东亚人中最大系列NC的临床病理特征以及NC细胞系中对MYC靶向剂的临床前敏感性。NC患者的预后严重,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(PI3K/HDAC双重抑制剂)对NC细胞最有效,随后是帕比司他(HDAC抑制剂)和AZD5153(二价BET抑制剂)。CUDC-907在NC治疗中可能是有希望的。
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.
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).
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.
East Asian patients with NUT carcinoma showed dismal survival outcomes like Western patients, and CUDC-907 might be promising in NUT carcinoma treatment.
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.