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

Toni Jauset1,2,3, Daniel Massó-Vallés1,2, Sandra Martínez-Martín1,2

  • 1Vall d'Hebron Institute of Oncology (VHIO), Edifici Cellex, Hospital Vall d'Hebron, Barcelona, Spain.

Oncotarget
|May 4, 2018
PubMed

Insights

Bromodomain and Extra-Terminal (BET) protein inhibition shows promise for treating KRAS-driven cancers like pancreatic ductal adenocarcinoma and non-small cell lung cancer. This approach effectively reduces tumor growth and cell proliferation, offering a new therapeutic avenue.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • KRAS-driven tumors, including pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), present significant treatment challenges.
  • Targeting downstream signaling effectors is a strategy to overcome limitations in directly inhibiting mutant KRAS.
  • Bromodomain and Extra-Terminal (BET) protein inhibition has demonstrated anti-tumor activity across various cancers.

Purpose of the Study:

  • To preclinically evaluate the efficacy of a novel BET inhibitor, BAY 1238097, against KRAS-driven PDAC and NSCLC models.
  • To assess the anti-tumor effects of BET inhibition both in vitro and in vivo.
  • To investigate the role of MYC expression in the anti-tumorigenic effects of BET inhibition.

Main Methods:

  • Utilized genetic mouse models of KRAS-driven PDAC and NSCLC for in vivo studies.
  • Tested BAY 1238097 on a panel of RAS-mutated human cancer cell lines (8 PDAC, 6 NSCLC) in vitro.
  • Assessed tumor area, tumor grade, cell number, and MYC expression levels.

Main Results:

  • BET inhibition with BAY 1238097 significantly reduced tumor area and grade in mouse models of KRAS-driven PDAC and NSCLC.
  • A significant reduction in cell number was observed in RAS-mutated human cancer cell lines treated with BAY 1238097.
  • While BET inhibition decreased MYC expression in some cell lines, its anti-tumor effect in PDAC cells was independent of MYC regulation.

Conclusions:

  • BET inhibition demonstrates significant therapeutic potential for KRAS-driven PDAC and NSCLC.
  • Further optimization of BET inhibitors is warranted to develop more effective and less toxic treatments for these malignancies.
  • The anti-tumorigenic effects of BET inhibition in PDAC may not be solely mediated by MYC downregulation.
Keywords:
BET inhibitionMYCNSCLCPDAC

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