Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study

Minsun Jung, Soyeon Kim, June Koo Lee, Sun Och Yoon, Heae Surng Park, Soon Won Hong, Weon Seo Park, Ji Eun Kim, Joon Kim, Bhumsuk Keam, Hyun Jik Kim, Hyoung Jin Kang, Dong Wan Kim, Kyeong Cheon Jung, Young Tae Kim, Dae Seog Heo, Tae Min Kim, Yoon Kyung Jeon

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)e740-e748
JournalOncologist
Volume24
Issue number8
DOIs
Publication statusPublished - 2019 Jan 1

Fingerprint

Multicenter Studies
Carcinoma
Histone Deacetylase Inhibitors
Inhibitory Concentration 50
Diagnostic Errors
Phosphatidylinositol 3-Kinases
Epidermal Growth Factor Receptor
Cell Line
Cell Death
Up-Regulation
Metastasectomy
Ligands
Chemoradiotherapy
Proxy
Therapeutics
Rare Diseases
Small Interfering RNA
Survivors
Neck
Immunohistochemistry

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Jung, M., Kim, S., Lee, J. K., Yoon, S. O., Park, H. S., Hong, S. W., ... Jeon, Y. K. (2019). Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study. Oncologist, 24(8), e740-e748. https://doi.org/10.1634/theoncologist.2018-0477
Jung, Minsun ; Kim, Soyeon ; Lee, June Koo ; Yoon, Sun Och ; Park, Heae Surng ; Hong, Soon Won ; Park, Weon Seo ; Kim, Ji Eun ; Kim, Joon ; Keam, Bhumsuk ; Kim, Hyun Jik ; Kang, Hyoung Jin ; Kim, Dong Wan ; Jung, Kyeong Cheon ; Kim, Young Tae ; Heo, Dae Seog ; Kim, Tae Min ; Jeon, Yoon Kyung. / Clinicopathological and Preclinical Findings of NUT Carcinoma : A Multicenter Study. In: Oncologist. 2019 ; Vol. 24, No. 8. pp. e740-e748.
@article{dcd20b46d99247719eeff6a24411ff00,
title = "Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study",
abstract = "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.",
author = "Minsun Jung and Soyeon Kim and Lee, {June Koo} and Yoon, {Sun Och} and Park, {Heae Surng} and Hong, {Soon Won} and Park, {Weon Seo} and Kim, {Ji Eun} and Joon Kim and Bhumsuk Keam and Kim, {Hyun Jik} and Kang, {Hyoung Jin} and Kim, {Dong Wan} and Jung, {Kyeong Cheon} and Kim, {Young Tae} and Heo, {Dae Seog} and Kim, {Tae Min} and Jeon, {Yoon Kyung}",
year = "2019",
month = "1",
day = "1",
doi = "10.1634/theoncologist.2018-0477",
language = "English",
volume = "24",
pages = "e740--e748",
journal = "Oncologist",
issn = "1083-7159",
publisher = "AlphaMed Press",
number = "8",

}

Jung, M, Kim, S, Lee, JK, Yoon, SO, Park, HS, Hong, SW, Park, WS, Kim, JE, Kim, J, Keam, B, Kim, HJ, Kang, HJ, Kim, DW, Jung, KC, Kim, YT, Heo, DS, Kim, TM & Jeon, YK 2019, 'Clinicopathological and Preclinical Findings of NUT Carcinoma: A Multicenter Study', Oncologist, vol. 24, no. 8, pp. e740-e748. https://doi.org/10.1634/theoncologist.2018-0477

Clinicopathological and Preclinical Findings of NUT Carcinoma : A Multicenter Study. / Jung, Minsun; Kim, Soyeon; Lee, June Koo; Yoon, Sun Och; Park, Heae Surng; Hong, Soon Won; Park, Weon Seo; Kim, Ji Eun; Kim, Joon; Keam, Bhumsuk; Kim, Hyun Jik; Kang, Hyoung Jin; Kim, Dong Wan; Jung, Kyeong Cheon; Kim, Young Tae; Heo, Dae Seog; Kim, Tae Min; Jeon, Yoon Kyung.

In: Oncologist, Vol. 24, No. 8, 01.01.2019, p. e740-e748.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Clinicopathological and Preclinical Findings of NUT Carcinoma

T2 - A Multicenter Study

AU - Jung, Minsun

AU - Kim, Soyeon

AU - Lee, June Koo

AU - Yoon, Sun Och

AU - Park, Heae Surng

AU - Hong, Soon Won

AU - Park, Weon Seo

AU - Kim, Ji Eun

AU - Kim, Joon

AU - Keam, Bhumsuk

AU - Kim, Hyun Jik

AU - Kang, Hyoung Jin

AU - Kim, Dong Wan

AU - Jung, Kyeong Cheon

AU - Kim, Young Tae

AU - Heo, Dae Seog

AU - Kim, Tae Min

AU - Jeon, Yoon Kyung

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85060918590&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85060918590&partnerID=8YFLogxK

U2 - 10.1634/theoncologist.2018-0477

DO - 10.1634/theoncologist.2018-0477

M3 - Article

C2 - 30696721

AN - SCOPUS:85060918590

VL - 24

SP - e740-e748

JO - Oncologist

JF - Oncologist

SN - 1083-7159

IS - 8

ER -