EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumors to TopoII inhibitors

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EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumors to TopoII inhibitors

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Title: EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumors to TopoII inhibitors
Author: Fillmore, Christine M.; Xu, Chunxiao; Desai, Pooja T.; Berry, Joanne M.; Rowbotham, Samuel P.; Lin, Yi-Jang; Zhang, Haikuo; Marquez, Victor E.; Hammerman, Peter S.; Wong, Kwok-Kin; Kim, Carla F.

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Citation: Fillmore, C. M., C. Xu, P. T. Desai, J. M. Berry, S. P. Rowbotham, Y. Lin, H. Zhang, et al. 2014. “EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumors to TopoII inhibitors.” Nature 520 (7546): 239-242. doi:10.1038/nature14122. http://dx.doi.org/10.1038/nature14122.
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Abstract: SUMMARY Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide1. Chemotherapies such as the topoisomerase II inhibitor (TopoIIi) etoposide effectively reduce disease in a minority of NSCLC patients2,3; therefore, alternative drug targets, including epigenetic enzymes, are under consideration for therapeutic intervention4. A promising potential epigenetic target is the methyltransferase EZH2, which in the context of the Polycomb Repressive Complex 2 (PRC2) is well known to tri-methylate Histone H3 at lysine 27 (H3K27me3) and elicit gene silencing5. Here, we demonstrate that EZH2 inhibition (EZH2i) had differential effects on TopoIIi response of NSCLCs in vitro and in vivo. EGFR and BRG1 mutations were genetic biomarkers that predicted enhanced sensitivity to TopoIIi in response to EZH2i. BRG1 loss-of-function mutant tumors responded to EZH2i with increased S phase, anaphase bridging, apoptosis, and TopoIIi sensitivity. Conversely, EGFR and BRG1 wild-type tumors up-regulated BRG1 in response to EZH2i and ultimately became more resistant to TopoIIi. EGFR gain-of-function mutant tumors were also sensitive to dual EZH2i and TopoIIi, due to genetic antagonism between EGFR and BRG1. These findings suggest an exciting opportunity for precision medicine in the genetically complex disease of NSCLC.
Published Version: doi:10.1038/nature14122
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393352/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:23474066
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