Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice

Laura Soucek, Jonathan R. Whitfield, Nicole M. Sodir, Daniel Massó-Vallés, Erika Serrano, Anthony Karnezis, Lamorna Brown Swigart, Gerard I. Evan

Research output: Contribution to journalArticle

160 Scopus citations

Abstract

The principal reason for failure of targeted cancer therapies is the emergence of resistant clones that regenerate the tumor. Therapeutic efficacy therefore depends on not only how effectively a drug inhibits its target, but also the innate or adaptive functional redundancy of that target and its attendant pathway. In this regard, the Myc transcription factors are intriguing therapeutic targets because they serve the unique and irreplaceable role of coordinating expression of the many diverse genes that, together, are required for somatic cell proliferation. Furthermore, Myc expression is deregulated in most-perhaps all-cancers, underscoring its irreplaceable role in proliferation.We previously showed in a preclinical mouse model of non-small-cell lung cancer that systemic Myc inhibition using the dominant-negative Myc mutant Omomyc exerts a dramatic therapeutic impact, triggering rapid regression of tumors with only mild and fully reversible side effects. Using protracted episodic expression of Omomyc, we now demonstrate that metronomic Myc inhibition not only contains Ras-driven lung tumors indefinitely, but also leads to their progressive eradication. Hence, Myc does indeed serve a unique and nondegenerate role in lung tumor maintenance that cannot be complemented by any adaptive mechanism, even in the most aggressive p53-deficient tumors. These data endorse Myc as a compelling cancer drug target.

Original languageEnglish (US)
Pages (from-to)504-513
Number of pages10
JournalGenes and Development
Volume27
Issue number5
DOIs
StatePublished - Mar 1 2013
Externally publishedYes

Keywords

  • Cancer therapy
  • Lung cancer
  • Mouse model
  • Myc

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Soucek, L., Whitfield, J. R., Sodir, N. M., Massó-Vallés, D., Serrano, E., Karnezis, A., Swigart, L. B., & Evan, G. I. (2013). Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes and Development, 27(5), 504-513. https://doi.org/10.1101/gad.205542.112