Modeling oncogene addiction using RNA interference.

Proceedings of the National Academy of Sciences of the United States of America
S Michael RothenbergJeffrey Settleman

Abstract

The clinical efficacy of selective kinase inhibitors suggests that some cancer cells may become dependent on a single oncogene for survival. RNAi has been increasingly used to understand such "oncogene addiction" and validate new therapeutic targets. However, RNAi approaches suffer from significant off-target effects that limit their utility. Here, we combine carefully titrated lentiviral-mediated short hairpin RNA knockdown of the epidermal growth factor receptor (EGFR) with heterologous reconstitution by EGFR mutants to rigorously analyze the structural features and signaling activities that determine addiction to the mutationally activated EGFR in human lung cancer cells. EGFR dependence is differentially rescued by distinct EGFR variants and oncogenic mutants, is critically dependent on its heterodimerization partner ErbB-3, and surprisingly, does not require autophosphorylation sites in the cytoplasmic domain. Quantitative "oncogene rescue" analysis allows mechanistic dissection of oncogene addiction, and, when broadly applied, may provide functional validation for potential therapeutic targets identified through large-scale RNAi screens.

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Citations

Mar 20, 2010·Digestive Diseases and Sciences·Kaushik MukherjeeWael El-Rifai
May 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Miguel N RiveraDaniel A Haber
Apr 18, 2012·Genes & Development·Gavin P DunnWilliam C Hahn
Mar 25, 2011·Science Translational Medicine·Lecia V SequistJeffrey A Engelman
Sep 9, 2011·Science Translational Medicine·Kimio YonesakaPasi A Jänne
Apr 22, 2010·Journal of Translational Medicine·Paolo A AsciertoMario Sznol
Jan 1, 2009·OncoTargets and Therapy·Charu Aggarwal, Hossein Borghaei
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Aug 30, 2008·Experimental Cell Research·Sreenath V Sharma, Jeffrey Settleman
May 18, 2011·Journal of Experimental & Clinical Cancer Research : CR·Wei YanTao Jiang
Aug 21, 2013·Biomaterials·Chetan YewaleAmbikanandan Misra
Feb 22, 2018·International Journal of Cancer. Journal International Du Cancer·Jeonghee ChoMatthew Meyerson
Feb 25, 2009·Expert Opinion on Therapeutic Targets·Elizabeth A Hopper-BorgeIgor Astsaturov

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