The GATA2 Transcriptional Network Is Requisite for RAS Oncogene-Driven Non-Small Cell Lung Cancer
Menée à l'aide d'un modèle murin, cette étude met en évidence le rôle joué par le facteur de transcription GATA2 dans les cellules de cancer du poumon non à petites cellules présentant des mutations du gène RAS
Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer deaths worldwide; nearly half contain mutations in the receptor tyrosine kinase/RAS pathway. Here we show that RAS-pathway mutant NSCLC cells depend on the transcription factor GATA2. Loss of GATA2 reduced the viability of NSCLC cells with RAS-pathway mutations, whereas wild-type cells were unaffected. Integrated gene expression and genome occupancy analyses revealed GATA2 regulation of the proteasome, and IL-1-signaling, and Rho-signaling pathways. These pathways were functionally significant, as reactivation rescued viability after GATA2 depletion. In a Kras-driven NSCLC mouse model, Gata2 loss dramatically reduced tumor development. Furthermore, Gata2 deletion in established Kras mutant tumors induced striking regression. Although GATA2 itself is likely undruggable, combined suppression of GATA2-regulated pathways with clinically approved inhibitors caused marked tumor clearance. Discovery of the nononcogene addiction of KRAS mutant lung cancers to GATA2 presents a network of druggable pathways for therapeutic exploitation. º GATA2 is essential for RAS-pathway mutant non-small cell lung cancer (NSCLC) º Gene expression and ChIP-seq studies reveal a GATA2 transcriptional network in NSCLC º Gata2 loss suppresses tumor growth in autochthonous models of Kras mutant NSCLC º Combined drug inhibition of GATA2-regulated pathways suppresses Kras mutant tumors Lung tumors with mutations in the RAS pathway are dependent on the transcription factor GATA2. Analysis of the GATA2 transcriptional network reveals components that when targeted in combination cause regression of KRAS-driven lung tumors in mice.
Cell 2012