Non-small cell lung cancer (NSCLC) is the most prevalent histological cancer subtype in terms of both incidence and mortality, with nearly 1.4 million deaths per year worldwide. Nearly one-third of all NSCLCs have activating mutations in the KRAS oncogene. In spite of thirty years' knowledge of KRAS mutations in lung cancer, it has proven therapeutically intractable, leaving KRAS mutant NSCLC to serve as a marker of poor prognosis. Thus, there is a substantial unmet clinical need to find treatment options for this subset of lung cancers.
By RNA interference screening, we previously discovered a transcription factor, GATA2, is necessary for the survival of KRAS mutant lung cancer cells, but not wild type lung cancer cells. Through an integrative genomic analysis of gene expression and chromatin occupancy, we discovered a GATA2-regulated transcriptional network consisting of the proteasome, IL-1 and Rho pathways. Functional analyses revealed that each of these pathways, though not individually necessary, is partially sufficient to restore viability in response to GATA2 depletion. Using two different genetically engineered mouse models (GEMMs), we found Gata2 is necessary for oncogenic Kras driven lung tumourigenesis. In addition, systemic Gata2 loss, while well tolerated, significantly extended survival in a Kras mutant NSCLC GEMM. Intriguingly, we found that combined treatment of Kras driven mouse models with clinically available inhibitors of the proteasome (bortezomib) and Rho kinase (fasudil) induced tumour regression.
We have now begun exploring and extending these initial therapeutic strategies to the Kras; Trp53 (KP) mouse model. Upon delivery of Cre recombinase to the lungs, KP mice undergo progression from low-grade adenomas to high-grade, invasive metastatic lung adenocarcinoma, more faithfully recapitulating the human disease. We have assessed our GATA2 network therapies through in vivo imaging of incipient lesions by micro-computed tomography, treatment cycles and subsequent re-imaging to determine efficacy. Using this approach, we observed substantial response when combining treatment with bortezomib and fasudil in the KP model. Moreover, introduction of a next-generation inhibitor of Rho kinase (AT13148), an agent in early-stage clinical development, combines with bortezomib to cause significant regression of lung adenocarcinomas in vivo. Taken together, we have elucidated a gene expression network necessary for Ras-driven lung cancer and have devised novel approaches to suppress this network with therapeutically tractable agents.
This abstract is also presented as Poster A14.
Citation Format: Madhu S. Kumar, Julian Downward. Targeting the GATA2 transcriptional network in K-Ras driven lung adenocarcinoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr PR14.
- ©2013 American Association for Cancer Research.