BET inhibition is an effective approach against KRAS-driven PDAC and NSCLC

Toni Jauset, Daniel Massó-Vallés, Sandra Martínez-Martín, Marie Eve Beaulieu, Laia Foradada, Francesco Paolo Fiorentino, Jun Yokota, Bernard Haendler, Stephan Siegel, Jonathan R. Whitfield, Laura Soucek

Research output: Contribution to journalArticleResearchpeer-review

6 Citations (Scopus)

Abstract

© Jauset et al. 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.
Original languageEnglish
Pages (from-to)18734-18746
JournalOncotarget
Volume9
Issue number27
DOIs
Publication statusPublished - 10 Apr 2018

Keywords

  • BET inhibition
  • MYC
  • NSCLC
  • PDAC

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