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CtBP—a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma

Ctbp2 is a uniquely targetable oncogenic transcriptional coregulator, exhibiting overexpression in most common solid tumors, and critical to the tumor-initiating cell (TIC) transcriptional program. In the “CKP” mouse pancreatic ductal adenocarcinoma (PDAC) model driven by mutant K-Ras, Ctbp2 haploin...

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Autores principales: Chawla, Ayesha T., Chougoni, Kranthi Kumar, Joshi, Prashant J., Cororaton, Agnes D., Memari, Patrick, Stansfield, John C., Park, Haemin, Seth, Rashmi, Szomju, Barbara, Sima, Adam P., Idowu, Michael O., Ellis, Keith C., Grossman, Steven R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778071/
https://www.ncbi.nlm.nih.gov/pubmed/31586042
http://dx.doi.org/10.1038/s41389-019-0163-x
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author Chawla, Ayesha T.
Chougoni, Kranthi Kumar
Joshi, Prashant J.
Cororaton, Agnes D.
Memari, Patrick
Stansfield, John C.
Park, Haemin
Seth, Rashmi
Szomju, Barbara
Sima, Adam P.
Idowu, Michael O.
Ellis, Keith C.
Grossman, Steven R.
author_facet Chawla, Ayesha T.
Chougoni, Kranthi Kumar
Joshi, Prashant J.
Cororaton, Agnes D.
Memari, Patrick
Stansfield, John C.
Park, Haemin
Seth, Rashmi
Szomju, Barbara
Sima, Adam P.
Idowu, Michael O.
Ellis, Keith C.
Grossman, Steven R.
author_sort Chawla, Ayesha T.
collection PubMed
description Ctbp2 is a uniquely targetable oncogenic transcriptional coregulator, exhibiting overexpression in most common solid tumors, and critical to the tumor-initiating cell (TIC) transcriptional program. In the “CKP” mouse pancreatic ductal adenocarcinoma (PDAC) model driven by mutant K-Ras, Ctbp2 haploinsufficiency prolonged survival, abrogated peritoneal metastasis, and caused dramatic downregulation of c-Myc, a known critical dependency for TIC activity and tumor progression in PDAC. A small-molecule inhibitor of CtBP2, 4-chloro-hydroxyimino phenylpyruvate (4-Cl-HIPP) phenocopied Ctbp2 deletion, decreasing tumor burden similarly to gemcitabine, and the combination of 4-Cl-HIPP and gemcitabine further synergistically suppressed tumor growth. Pharmacodynamic monitoring revealed that the 4-Cl-HIPP/gemcitabine combination induced robust and synergistic tumor apoptosis and marked downregulation of the TIC marker CD133 in CKP PDAC tumors. Collectively, our data demonstrate that targeting CtBP represents a fruitful avenue for development of highly active agents in PDAC that cooperate with standard therapy to limit both primary and metastatic tumor burden.
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spelling pubmed-67780712019-10-07 CtBP—a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma Chawla, Ayesha T. Chougoni, Kranthi Kumar Joshi, Prashant J. Cororaton, Agnes D. Memari, Patrick Stansfield, John C. Park, Haemin Seth, Rashmi Szomju, Barbara Sima, Adam P. Idowu, Michael O. Ellis, Keith C. Grossman, Steven R. Oncogenesis Brief Communication Ctbp2 is a uniquely targetable oncogenic transcriptional coregulator, exhibiting overexpression in most common solid tumors, and critical to the tumor-initiating cell (TIC) transcriptional program. In the “CKP” mouse pancreatic ductal adenocarcinoma (PDAC) model driven by mutant K-Ras, Ctbp2 haploinsufficiency prolonged survival, abrogated peritoneal metastasis, and caused dramatic downregulation of c-Myc, a known critical dependency for TIC activity and tumor progression in PDAC. A small-molecule inhibitor of CtBP2, 4-chloro-hydroxyimino phenylpyruvate (4-Cl-HIPP) phenocopied Ctbp2 deletion, decreasing tumor burden similarly to gemcitabine, and the combination of 4-Cl-HIPP and gemcitabine further synergistically suppressed tumor growth. Pharmacodynamic monitoring revealed that the 4-Cl-HIPP/gemcitabine combination induced robust and synergistic tumor apoptosis and marked downregulation of the TIC marker CD133 in CKP PDAC tumors. Collectively, our data demonstrate that targeting CtBP represents a fruitful avenue for development of highly active agents in PDAC that cooperate with standard therapy to limit both primary and metastatic tumor burden. Nature Publishing Group UK 2019-10-04 /pmc/articles/PMC6778071/ /pubmed/31586042 http://dx.doi.org/10.1038/s41389-019-0163-x Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Brief Communication
Chawla, Ayesha T.
Chougoni, Kranthi Kumar
Joshi, Prashant J.
Cororaton, Agnes D.
Memari, Patrick
Stansfield, John C.
Park, Haemin
Seth, Rashmi
Szomju, Barbara
Sima, Adam P.
Idowu, Michael O.
Ellis, Keith C.
Grossman, Steven R.
CtBP—a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma
title CtBP—a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma
title_full CtBP—a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma
title_fullStr CtBP—a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma
title_full_unstemmed CtBP—a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma
title_short CtBP—a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma
title_sort ctbp—a targetable dependency for tumor-initiating cell activity and metastasis in pancreatic adenocarcinoma
topic Brief Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778071/
https://www.ncbi.nlm.nih.gov/pubmed/31586042
http://dx.doi.org/10.1038/s41389-019-0163-x
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