| First Author | Choi PS | Year | 2014 |
| Journal | Proc Natl Acad Sci U S A | Volume | 111 |
| Issue | 32 | Pages | E3316-24 |
| PubMed ID | 25071175 | Mgi Jnum | J:213704 |
| Mgi Id | MGI:5585655 | Doi | 10.1073/pnas.1406123111 |
| Citation | Choi PS, et al. (2014) Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance. Proc Natl Acad Sci U S A 111(32):E3316-24 |
| abstractText | 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. |
