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Fillmore, Christine M.

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Fillmore

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Christine M.

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Fillmore, Christine M.

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20142

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Author's Publications: search.filters.isAuthorOfPublication.7a9b853c-7539-40a4-9011-a303e2616465

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    EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumors to TopoII inhibitors
    (2014) Fillmore, Christine M.; Xu, Chunxiao; Desai, Pooja T.; Berry, Joanne M.; Rowbotham, Samuel; Lin, Yi-Jang; Zhang, Haikuo; Marquez, Victor E.; Hammerman, Peter S.; Wong, Kwok-Kin; Kim, Carla
    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.
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    Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated PD-L1 Expression
    (Elsevier BV, 2014-05) Xu, Chunxiao; Fillmore, Christine M.; Koyama, Shohei; Hongbo, Wu; Zhao, Yanqiu; Chen, Zhao; Herter Sprie, Grit; Akbay, Esra A.; Tchaicha, Jeremy; Altabef, Abigail; Reibel, Jacob; Walton, Zandra; Ji, Hongbin; Watanabe, Hideo; Janne, Pasi; Castrillon, Diego H.; Rustgi, Anil K.; Bass, Adam; Freeman, Gordon; Padera, Robert; Dranoff, Glenn; Hammerman, Peter S.; Kim, Carla F.; Wong, Kwok-Kin; Hammerman
    Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate. We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease. Lkb1;Pten null (LP) tumors expressed the squamous markers KRT5, p63 and SOX2, and transcriptionally resembled the basal subtype of human SCC. In contrast to mouse adenocarcinomas, the LP tumors contained immune populations enriched for tumor-associated neutrophils. SCA1+NGFR+ fractions were enriched for tumor-propagating cells (TPCs) that could serially transplant the disease in orthotopic assays. TPCs in the LP model and NGFR+ cells in human SCCs highly expressed Pd-ligand-1 (PD-L1), suggesting a mechanism of immune escape for TPCs.