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Experimental and Molecular Therapeutics

Abstract 1256: Multi-focal control of mitochondrial gene expression by oncogenic MYC provides effective therapeutic targets in cancer

Amanda Taylor, Clare Adams, Xiao-yong Zhang, Victoria Gennaro, Justin Cotney, Gerald Shadel, Craig Cameron, Christine Eischen and Steven McMahon
Amanda Taylor
Thomas Jefferson University, Philadelphia, PA;
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Clare Adams
Vanderbilt University, Nashville, TN;
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Xiao-yong Zhang
Thomas Jefferson University, Philadelphia, PA;
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Victoria Gennaro
Thomas Jefferson University, Philadelphia, PA;
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Justin Cotney
Yale University School of Medicine, New Haven, CT;
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Gerald Shadel
Yale University School of Medicine, New Haven, CT;
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Craig Cameron
Pennsylvania State University, University Park, PA.
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Christine Eischen
Vanderbilt University, Nashville, TN;
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Steven McMahon
Thomas Jefferson University, Philadelphia, PA;
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DOI: 10.1158/1538-7445.AM2016-1256 Published July 2016
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Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA

Abstract

The MYC transcription factor is the most dramatically overexpressed gene product in human cancer. However, defining the MYC-driven transcriptome critical to malignant transformation has remained a challenge, in part because MYC controls several thousand genes. Consequently, little progress has been made in the identification of sensitive nodes downstream of MYC that might be targeted therapeutically in order to interrupt its oncogenic signaling. To overcome this impediment, we performed a screen for downstream MYC effector pathways that are selectively linked to MYC's functional properties. Via this strategy, we identified the mitochondrial RNA polymerase (POLRMT) as a direct downstream target of MYC. POLRMT induction by MYC regulates transcription of the mitochondrial genome, as well as mitochondrial DNA replication. Recent studies have shown that POLRMT also interacts with a mitochondrial ribosomal RNA methyltransferase TFB1M to regulate mitochondrial ribosome assembly. Notably, blocking induction of POLRMT (or TFB1M) by MYC converts the cellular response to MYC activation from enhanced cell cycle progression to apoptotic cell death. Of immediate clinical relevance, compounds blocking mitochondrial gene expression at any of several steps cause acute synthetic lethality with oncogenic levels of MYC. Among these compounds, the mitochondrial targeting antibiotic Tigecycline is FDA-approved and well-tolerated in patients. Tigecycline eliminates tumor formation and dramatically improves survival in our animal model of MYC-driven lymphoma. Evidence presented here demonstrates that uncoupling of MYC's nuclear and mitochondrial transcriptomes exposes a point of exquisite vulnerability in tumor cells. Although targeting MYC as a therapeutic strategy has proven to be challenging in the past, our identification of a new node of sensitivity in MYC-driven cancers offers a potential for broad therapeutic implications.

Citation Format: Amanda Taylor, Clare Adams, Xiao-yong Zhang, Victoria Gennaro, Justin Cotney, Gerald Shadel, Craig Cameron, Christine Eischen, Steven McMahon. Multi-focal control of mitochondrial gene expression by oncogenic MYC provides effective therapeutic targets in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1256.

  • ©2016 American Association for Cancer Research.
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Cancer Research: 76 (14 Supplement)
July 2016
Volume 76, Issue 14 Supplement
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Abstract 1256: Multi-focal control of mitochondrial gene expression by oncogenic MYC provides effective therapeutic targets in cancer
Amanda Taylor, Clare Adams, Xiao-yong Zhang, Victoria Gennaro, Justin Cotney, Gerald Shadel, Craig Cameron, Christine Eischen and Steven McMahon
Cancer Res July 15 2016 (76) (14 Supplement) 1256; DOI: 10.1158/1538-7445.AM2016-1256

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Abstract 1256: Multi-focal control of mitochondrial gene expression by oncogenic MYC provides effective therapeutic targets in cancer
Amanda Taylor, Clare Adams, Xiao-yong Zhang, Victoria Gennaro, Justin Cotney, Gerald Shadel, Craig Cameron, Christine Eischen and Steven McMahon
Cancer Res July 15 2016 (76) (14 Supplement) 1256; DOI: 10.1158/1538-7445.AM2016-1256
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Cancer Research Online ISSN: 1538-7445
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