Ετικέτες

Τρίτη 29 Ιανουαρίου 2019

Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study

AbstractBackground.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.

http://bit.ly/2Ru5y4M

Δεν υπάρχουν σχόλια:

Δημοσίευση σχολίου

Αναζήτηση αυτού του ιστολογίου