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Proc Natl Acad Sci U S A. 2014 Aug 12;111(32):E3316-24. doi: 10.1073/pnas.1406123111. Epub 2014 Jul 28.

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

Author information

1
Division of Oncology, Departments of Medicine, Pathology, and Molecular Imaging, Stanford University School of Medicine, Stanford, CA 94305.
2
Division of Oncology, Departments of Medicine, Pathology, and Molecular Imaging, Stanford University School of Medicine, Stanford, CA 94305 dfelsher@stanford.edu.

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.

KEYWORDS:

combination targeted therapy; oncogene addiction; splice site mutations

PMID:
25071175
PMCID:
PMC4136575
DOI:
10.1073/pnas.1406123111
[Indexed for MEDLINE]
Free PMC Article

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