BET inhibition is an effective approach against KRAS-driven PDAC and NSCLC
Jauset González, Toni (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Massó Vallés, Daniel (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Martínez Martín, Sandra (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Beaulieu, Marie-Eve (Vall d'Hebron Institut d'Oncologia)
Foradada Felip, Laia (Vall d'Hebron Institut d'Oncologia)
Fiorentino, Francesco Paolo (Department of Biomedical Sciences, University of Sassari)
Yokota, Jun (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Haendler, Bernard (Drug Discovery, Bayer AG)
Siegel, Stephan (Drug Discovery, Bayer AG)
Whitfield, Jonathan R. (Vall d'Hebron Institut d'Oncologia)
Soucek, Laura (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2018
Abstract:	Effectively treating KRAS-driven tumors remains an unsolved challenge. The inhibition of downstream signaling effectors is a way of overcoming the issue of direct targeting of mutant KRAS, which has shown limited efficacy so far. Bromodomain and Extra-Terminal (BET) protein inhibition has displayed anti-tumor activity in a wide range of cancers, including KRAS-driven malignancies. Here, we preclinically evaluate the effect of BET inhibition making use of a new BET inhibitor, BAY 1238097, against Pancreatic Ductal Adenocarcinoma (PDAC) and Non-Small Cell Lung Cancer (NSCLC) models harboring RAS mutations both in vivo and in vitro. Our results demonstrate that BET inhibition displays significant therapeutic impact in genetic mouse models of KRAS-driven PDAC and NSCLC, reducing both tumor area and tumor grade. The same approach also causes a significant reduction in cell number of a panel of RAS-mutated human cancer cell lines (8 PDAC and 6 NSCLC). In this context, we demonstrate that while BET inhibition by BAY 1238097 decreases MYC expression in some cell lines, at least in PDAC cells its anti-tumorigenic effect is independent of MYC regulation. Together, these studies reinforce the use of BET inhibition and prompt the optimization of more efficient and less toxic BET inhibitors for the treatment of KRAS-driven malignancies, which are in urgent therapeutic need.
Grants:	European Commission 617473 Instituto de Salud Carlos III FIS/PI13-01705 Agència de Gestió d'Ajuts Universitaris i de Recerca 2014/SGR-1171
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	BET inhibition ; MYC ; PDAC ; NSCLC
Published in:	Oncotarget, Vol. 9 (april 2018) , p. 18734-18746, ISSN 1949-2553

DOI: 10.18632/oncotarget.24648
PMID: 29721157

13 p, 5.3 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
Articles > Research articles
Articles > Published articles