title: 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.
authors.affiliation: Signal Transduction Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Madhu S
authors.initials: MS
authors.lastname: Kumar
authors.forename: David C
authors.initials: DC
authors.lastname: Hancock
authors.forename: Miriam
authors.initials: M
authors.lastname: Molina-Arcas
authors.forename: Michael
authors.initials: M
authors.lastname: Steckel
authors.forename: Phillip
authors.initials: P
authors.lastname: East
authors.forename: Markus
authors.initials: M
authors.lastname: Diefenbacher
authors.forename: Elena
authors.initials: E
authors.lastname: Armenteros-Monterroso
authors.forename: François
authors.initials: F
authors.lastname: Lassailly
authors.forename: Nik
authors.initials: N
authors.lastname: Matthews
authors.forename: Emma
authors.initials: E
authors.lastname: Nye
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Axel
authors.initials: A
authors.lastname: Behrens
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; C494712:Gata2 protein, mouse; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins