title: Addiction to multiple oncogenes can be exploited to prevent the emergence of therapeutic resistance.
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.
authors: Division of Oncology, Departments of Medicine, Pathology, and Molecular Imaging, Stanford University School of Medicine, Stanford, CA 94305.
authors: Peter S
authors: PS
authors: Choi
authors: Division of Oncology, Departments of Medicine, Pathology, and Molecular Imaging, Stanford University School of Medicine, Stanford, CA 94305.
authors: Yulin
authors: Y
authors: Li
authors: Division of Oncology, Departments of Medicine, Pathology, and Molecular Imaging, Stanford University School of Medicine, Stanford, CA 94305 dfelsher@stanford.edu.
authors: Dean W
authors: DW
authors: Felsher
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D016259:Genes, myc / Q000187:drug effects; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism; D009857:Oncogenes / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D022821:RNA Splice Sites; D051020:bcl-X Protein / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C494812:Bcl2l1 protein, mouse; C000606776:Bcl2l11 protein, mouse; C495267:CTNNB1 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D022821:RNA Splice Sites; D051020:bcl-X Protein; D051176:beta Catenin
keywords: combination targeted therapy; oncogene addiction; splice site mutations