The GATA2 Transcriptional Network Is Requisite for RAS Oncogene-Driven Non-Small Cell Lung Cancer

Abstract

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.

Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells

“…However, dissecting the downstream genetic dependencies that constitute Ras addiction has proved more complex. Several genome-wide screens against the KRAS oncogene have identified a surprisingly diverse set of genes whose depletion causes greater toxicity in KRAS mutant cells compared with KRAS WT cells (6,(35)(36)(37)(38)(39). We think that this finding reflects a broad dependency of Ras mutant cells on various stress relief pathways that constitute what we termed nononcogene addictions (7).…”

CDK9-mediated transcription elongation is required for MYC addiction in hepatocellular carcinoma

“…Our study used experimental RNAi to identify genes that are selectively required for the proliferation or survival of cancer cells (Ashworth and Bernards 2010;Kessler et al 2012;Kumar et al 2012). We designed a focused shRNA library to identify small molecules that could be repurposed for new applications such as treatment of HCC.…”

“…RNAi technology enables a systematic interrogation of genes whose loss of function affects cell proliferation and viability (Ashworth and Bernards 2010;Kessler et al 2012;Kumar et al 2012). While a powerful method for identifying novel therapeutic targets, genome-wide RNAi screens can be laborious and expensive, requiring substantial infrastructure and specialized expertise for their execution.…”

149 Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS-mutant Cancer Models

“…Investigators have identified potential therapeutic approaches for KRAS mutant cancers that are yet to be explored in the clinic, including inhibitors of TBK1, TAK1, and the GATA2 transcriptional network Singh et al, 2012;Kumar et al, 2012). Previously, our laboratory and others showed that simultaneous targeting of more than one KRAS effector pathway (specifically the MEK-ERK and PI3K-AKT pathways) induced responses in KRAS-driven mouse tumor models (Engelman et al, 2008;She et al, 2010).…”