Browsing by Author "Draetta, Giulio F."

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    EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming
    (Cancer Research, 2017-12-01) Adelaiye-Ogala, Remi; Budka, Justin; Damayanti, Nur P.; Arrington, Justine; Ferris, Mary; Hsu, Chuan-Chih; Chintala, Sreenivasulu; Orillion, Ashley; Miles, Kiersten Marie; Shen, Li; Elbanna, May; Ciamporcero, Eric; Arisa, Sreevani; Pettazzoni, Piergiorgio; Draetta, Giulio F.; Seshadri, Mukund; Hancock, Bradley; Radovich, Milan; Kota, Janaiah; Buck, Michael; Keilhack, Heike; McCarthy, Brian P.; Persohn, Scott A.; Territo, Paul R.; Zang, Yong; Irudayaraj, Joseph; Tao, W. Andy; Hollenhorst, Peter; Pili, Roberto
    Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represent a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft (PDX) model that is intrinsically resistant to the RTKI sunitinib but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its anti-angiogenic and anti-metastatic activity but lost its direct anti-tumor effects due to kinome reprogramming, which resulted in suppression of pro- apoptotic and cell cycle regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTK, restoring the anti-tumor effects of sunitnib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease.
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    The mutational landscape and functional effects of noncoding ultraconserved elements in human cancers
    (American Association for the Advancement of Science, 2025) Bayraktar, Recep; Tang, Yitao; Dragomir, Mihnea P.; Ivan, Cristina; Peng, Xinxin; Fabris, Linda; Zhang, Jianhua; Carugo, Alessandro; Aneli, Serena; Liu, Jintan; Chen, Mei-Ju M.; Srinivasan, Sanjana; Sahnoune, Iman; Bayraktar, Emine; Akdemir, Kadir C.; Chen, Meng; Narayanan, Pranav; Huang, Wilson; Ott, Leonie Florence; Eterovic, Agda Karina; Villarreal, Oscar Eduardo; Mohammad, Mohammad Moustaf; Peoples, Michael D.; Walsh, Danielle M.; Hernandez, Jon Andrew; Morgan, Margaret B.; Shaw, Kenna R.; Davis, Jennifer S.; Menter, David; Tam, Constantine S.; Yeh, Paul; Dawson, Sarah-Jane; Rassenti, Laura Z.; Kipps, Thomas J.; Kunej, Tanja; Estrov, Zeev; Joosse, Simon A.; Pagani, Luca; Alix-Panabières, Catherine; Pantel, Klaus; Ferajoli, Alessandra; Futreal, Andrew; Wistuba, Ignacio I.; Radovich, Milan; Kopetz, Scott; Keating, Michael J.; Draetta, Giulio F.; Mattick, John S.; Liang, Han; Calin, George A.; Surgery, School of Medicine
    The mutational landscape of phylogenetically ultraconserved elements (UCEs), especially those in noncoding DNAs (ncUCEs), and their functional relevance in cancers remain poorly characterized. Here, we perform a systematic analysis of whole-genome and in-house targeted UCE sequencing datasets from more than 3000 patients with cancer of 13,736 UCEs and demonstrate that ncUCE somatic alterations are common. Using a multiplexed CRISPR knockout screen in colorectal cancer cells, we show that the loss of several altered ncUCEs significantly affects cell proliferation. In-depth functional studies in vitro and in vivo further reveal that specific ncUCEs can be enhancers of tumor suppressors (such as ARID1B) and silencers of oncogenic proteins (such as RPS13). Moreover, several miRNAs located in ncUCEs are recurrently mutated. Mutations in miR-142 locus can affect the Drosha-mediated processing of precursor miRNAs, resulting in the down-regulation of the mature transcript. These results provide systematic evidence that specific ncUCEs play diverse regulatory roles in cancer.