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

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

doi:10.18632/oncotarget.24648

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.

Highlights

Mutation in the KRAS oncogene is one of the most frequent events in human cancers
In order to preclinically assess the in vivo efficacy of Bromodomain and Extra-Terminal (BET) inhibition by BAY 1238097 in an immunocompetent context, we made use of two wellcharacterized KRAS-driven genetically engineered mouse models of Pancreatic Ductal Adenocarcinoma (PDAC) (LSL-KrasG12D;Pdx1-Cre;p53ER/ER) and Non-Small Cell Lung Cancer (NSCLC) (LSL-KrasG12D;p53ER/ER) [23, 24]
In the PDAC model, Cre recombinase is placed under the control of the Pdx1 promoter, which is activated in progenitor cells of mouse pancreas [23], while in the NSCLC model, adenocarcinomas are generated focally in the lung epithelium by delivering CRE recombinase through intranasal instillation of adenoviruses (Ad-Cre) [24]

Summary

Introduction

Mutation in the KRAS oncogene is one of the most frequent events in human cancers. In Non-Small Cell Lung Cancer (NSCLC), the main lung cancer subtype that accounts for the highest number of cancer-related deaths, KRAS is mutated in 30% of the cases [1]. These drugs have not proven to be effective against RASdriven cancers in patients far [6] In this context, some groups have recently demonstrated the therapeutic potential of Bromodomain and Extra-terminal (BET) protein inhibition in NSCLC and PDAC preclinical models [7,8,9,10,11,12]. The key role of BET bromodomains in cancer initiation and maintenance has been highlighted by the development of small molecule BET bromodomain inhibitors [13] Such inhibitors prevent the interaction between bromodomains and acetylated lysines, displaying significant anti-tumorigenic activity by regulating key engines of tumorigenesis like MYC [14, 15]. There is an increasing concern about the potential toxicity that BET inhibitors might display in normal tissues versus cancer cells [19]

Methods

Results

Conclusion