Kumar, M. S., Hancock, D. C., Molina-Arcas, M., Steckel, M., East, P., Diefenbacher, M., Armenteros-Monterroso, E., Lassailly, F., Matthews, N., Nye, E., Stamp, G., Behrens, A., Downward, J. (2012) The GATA2 Transcriptional Network Is Requisite for RAS Oncogene-Driven Non-Small Cell Lung Cancer. CELL, 149 (3). pp. 642-655. ISSN 0092-8674

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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.

Item Type:	Article
Authors (ICR Faculty only):	Downward, Julian
All Authors:	Kumar, M. S., Hancock, D. C., Molina-Arcas, M., Steckel, M., East, P., Diefenbacher, M., Armenteros-Monterroso, E., Lassailly, F., Matthews, N., Nye, E., Stamp, G., Behrens, A., Downward, J.
Additional Information:	ISI Document Delivery No.: 934KN Times Cited: 0 Cited Reference Count: 36 Kumar, Madhu S. Hancock, David C. Molina-Arcas, Miriam Steckel, Michael East, Phillip Diefenbacher, Markus Armenteros-Monterroso, Elena Lassailly, Francois Matthews, Nik Nye, Emma Stamp, Gordon Behrens, Axel Downward, Julian Cancer Research UK; European Commission[HEALTH-F2-2010-259770] We thank S. M. Henshall for the GATA2 expression vector; D. Finley for the USP14 expression vector; R. Deshaies for the Nrf1 expression vector; D. Goubau for the NF-kappa B and control reporter plasmids; E. Meylan and W. Xue for the RelA expression vector; E. Sahai for the RhoA and ROCK: ER expression vectors; and F. Gouilleux for the STAT5<SUP>CA</SUP> expression vector. We thank the LRI FACS facility for cell-cycle assays and the Bart's Genome Centre for gene expression analysis. We thank C. Sheridan for micro-CT assistance. M. S. K. is a Long-Term Fellow of the Human Frontier Science Program and European Molecular Biology Organization. M. M. is a Marie Curie Postdoctoral Fellow. This work was supported by Cancer Research UK and by funding from the European Commission's Seventh Framework Programme (FP7/2007-2013) under the Lungtarget Grant agreement (HEALTH-F2-2010-259770). Cell press Cambridge
Uncontrolled Keywords:	kappa-b k-ras activation expression mouse adenocarcinoma inhibition interleukin-1 carcinoma therapy
Research teams:	ICR divisions > Molecular Pathology > Lung Cancer Group
Depositing User:	Users 11 not found.
Date Deposited:	28 May 2012 09:29
Last Modified:	28 May 2012 11:37
URI:	http://publications.icr.ac.uk/id/eprint/11667

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