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The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer

Madhu S Kumar1, David C Hancock, Miriam Molina-Arcas

  • 1Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.

Cell
|May 1, 2012
PubMed

Insights

RAS-pathway mutations drive non-small cell lung cancer (NSCLC) dependence on GATA2. Targeting GATA2-regulated pathways offers a novel therapeutic strategy for KRAS-mutant lung cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality globally.
  • Approximately 50% of NSCLC cases harbor mutations in the receptor tyrosine kinase/RAS pathway.

Purpose of the Study:

  • To investigate the role of the transcription factor GATA2 in RAS-pathway mutant NSCLC.
  • To identify potential therapeutic targets within GATA2-regulated pathways.

Main Methods:

  • Gene expression and genome occupancy analyses were performed.
  • Functional significance of GATA2-regulated pathways was assessed.
  • A Kras-driven NSCLC mouse model was utilized to evaluate Gata2's role in tumor development and regression.

Main Results:

  • Loss of GATA2 selectively reduced the viability of RAS-pathway mutant NSCLC cells.
  • GATA2 was found to regulate proteasome, IL-1-signaling, and Rho-signaling pathways.
  • Gata2 loss significantly inhibited tumor development and induced regression in established Kras-mutant NSCLC tumors in mice.

Conclusions:

  • RAS-pathway mutant NSCLC exhibits a nononcogene addiction to GATA2.
  • Targeting GATA2-regulated pathways, even if GATA2 itself is undruggable, presents a promising therapeutic avenue.
  • Combined suppression of GATA2-dependent pathways with existing inhibitors led to significant tumor clearance in preclinical models.

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