Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance

Peter S. Choi, Yulin Li, Dean W. Felsher

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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 β-catenin, including a previously unreported mutation in a splice acceptor site. Tumors with these genetic lesions are highly dependent on β-catenin for their survival and the suppression of β-catenin resulted in marked apoptosis causally related to a decrease in Bcl-xL expression. Using a novel inducible inhibitor of β-catenin, we illustrate that, although MYC withdrawal or β-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 β-catenin promoted more rapid tumor regression and successfully prevented tumor recurrence. Hence, we demonstrated that MYC-induced tumors are addicted to mutant β-catenin, and the combined inactivation of MYC and β-catenin induces sustained tumor regression. Our results provide a proof of principle that targeting multiple oncogene addicted pathways can prevent therapeutic resistance.

Original languageEnglish (US)
Pages (from-to)E3316-E3324
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number32
DOIs
StatePublished - Aug 12 2014

Keywords

  • Combination targeted therapy
  • Oncogene addiction
  • Splice site mutations

ASJC Scopus subject areas

  • General

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