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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Apoptosis Regulatory Proteins / metabolism
  • Bcl-2-Like Protein 11
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm / genetics*
  • Genes, myc / drug effects
  • Lymphoma / drug therapy
  • Lymphoma / genetics
  • Lymphoma / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mice, SCID
  • Mice, Transgenic
  • Mutation
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / metabolism
  • Oncogenes* / drug effects
  • Proto-Oncogene Proteins / metabolism
  • RNA Splice Sites
  • bcl-X Protein / metabolism
  • beta Catenin / antagonists & inhibitors
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Apoptosis Regulatory Proteins
  • Bcl-2-Like Protein 11
  • Bcl2l1 protein, mouse
  • Bcl2l11 protein, mouse
  • CTNNB1 protein, mouse
  • Membrane Proteins
  • Proto-Oncogene Proteins
  • RNA Splice Sites
  • bcl-X Protein
  • beta Catenin