BET inhibition is an effective approach against KRAS-driven PDAC and NSCLC
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Toni Jauset1,2,3, Daniel Massó-Vallés1,2, Sandra Martínez-Martín1,2, Marie-Eve Beaulieu1,3, Laia Foradada1,3, Francesco Paolo Fiorentino4,5, Jun Yokota6, Bernard Haendler7, Stephan Siegel7, Jonathan R. Whitfield1 and Laura Soucek1,2,3,8
1Vall d’Hebron Institute of Oncology (VHIO), Edifici Cellex, Hospital Vall d’Hebron, Barcelona, Spain
2Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain
3Peptomyc S.L., Edifici Cellex, Hospital Vall d’Hebron, Barcelona, Spain
4Kitos Biotech srls, Porto Conte Ricerche, Alghero, Italy
5Department of Biomedical Sciences, University of Sassari, Sassari, Italy
6Genomics and Epigenomics of Cancer Prediction Program, Institut d’Investigació Germans Trias I Pujol (IGTP), Campus Can Ruti, Barcelona, Spain
7Drug Discovery, Bayer AG, Berlin, Germany
8Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
Laura Soucek, email: firstname.lastname@example.org
Keywords: BET inhibition; MYC; PDAC; NSCLC
Received: January 04, 2018 Accepted: February 25, 2018 Published: April 10, 2018
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.
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