Abstract
Deletion of Gata2 or inhibition of its targets induces regression of Kras-mutant NSCLC.
Major finding: Deletion of Gata2 or inhibition of its targets induces regression of Kras-mutant NSCLC.
Mechanism: GATA2 mediates survival through regulation of Rho and IL-1 signaling and the proteasome.
Impact: Inhibition of druggable GATA2 targets may be effective in KRAS-mutant lung cancers.
KRAS is one of the most commonly mutated genes in non–small cell lung cancer (NSCLC). Previous screens for genes necessary for KRAS-mutant NSCLC survival have generally not examined the systemic effects of targeting essential genes or whether inhibiting potential targets can induce regression of established tumors. In an RNAi screen, Kumar and colleagues identified the gene encoding the transcription factor GATA2 as specifically essential to KRAS-mutant NSCLC cell line survival both in vitro and in tumor xenografts. Simultaneous deletion of Gata2 and expression of mutant Kras in the lungs of mice also led to a significant decrease in the number of tumors formed. Importantly, whole-body deletion of Gata2 after Kras-mutant tumors had already formed was well tolerated and led to tumor regression in 100% of mice. Gene expression analysis following GATA2 knockdown in human NSCLC cells revealed that GATA2 is required for activation of a broad transcriptional network affecting the proteasome complex, interleukin-1 signaling, and the RHO pathway. Reactivation of any of these pathways after GATA2 knockdown partially rescued the viability of KRAS-mutant NSCLC cells, suggesting that KRAS-mutant cells are collectively dependent on these members of the GATA2 signaling network. Because transcription factors such as GATA2 are difficult to target with small molecules, the authors therefore tested whether combining clinically available proteasomal and Rho signaling pathway inhibitors would induce regression of established Kras-mutant murine lung tumors. Indeed, combined treatment with bortezomib, a proteasome inhibitor, and fasudil, a selective Rho pathway inhibitor, led to significant reductions in tumor burden, number, and size compared with either drug alone. This study thus identifies a form of nononcogene addiction in KRAS-mutant NSCLC and indicates that combined inhibition of GATA2 targets with clinically available small-molecule inhibitors may be an effective therapeutic strategy in these tumors.
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