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标题：Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance
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作者：Peter S. Choi ; Yulin Li ; Dean W. Felsher 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：32
页码：E3316-E3324
DOI：10.1073/pnas.1406123111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Many cancers exhibit sensitivity to the inhibition of a single genetic lesion, a property that has been successfully exploited with oncogene-targeted therapeutics. However, inhibition of single oncogenes often fails to result in sustained tumor regression due to the emergence of therapy-resistant cells. Here, we report that MYC-driven lymphomas frequently acquire activating mutations in {beta}-catenin, including a previously unreported mutation in a splice acceptor site. Tumors with these genetic lesions are highly dependent on {beta}-catenin for their survival and the suppression of {beta}-catenin resulted in marked apoptosis causally related to a decrease in Bcl-xL expression. Using a novel inducible inhibitor of {beta}-catenin, we illustrate that, although MYC withdrawal or {beta}-catenin inhibition alone results in initial tumor regression, most tumors ultimately recurred, mimicking the clinical response to single-agent targeted therapy. Importantly, the simultaneous combined inhibition of both MYC and {beta}-catenin promoted more rapid tumor regression and successfully prevented tumor recurrence. Hence, we demonstrated that MYC-induced tumors are addicted to mutant {beta}-catenin, and the combined inactivation of MYC and {beta}-catenin induces sustained tumor regression. Our results provide a proof of principle that targeting multiple oncogene addicted pathways can prevent therapeutic resistance.
关键词：oncogene addiction ; combination targeted therapy ; splice site mutations