Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase

Dun Yang, Hong Liu, Andrei Goga, Suwon Kim, Mariia Yuneva, J. Michael Bishop

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

The Myc protein and proteins that participate in mitosis represent attractive targets for cancer therapy. However, their potential is presently compromised by the threat of side effects and by a lack of pharmacological inhibitors of Myc. Here we report that a circumscribed exposure to the aurora kinase inhibitor, VX-680, selectively kills cells that overexpress Myc. This synthetic lethal interaction is attributable to inhibition of aurora-B kinase, with consequent disabling of the chromosomal passenger protein complex (CPPC) and ensuing DNA replication in the absence of cell division; executed by sequential apoptosis and autophagy; not reliant on the tumor suppressor protein p53; and effective against mouse models for B-cell and T-cell lymphomas initiated by transgenes of MYC. Our findings cast light on how inhibitors of aurora-B kinase may kill tumor cells, implicate Myc in the induction of a lethal form of autophagy, indicate that expression of Myc be a useful biomarker for sensitivity of tumor cells to inhibition of the CPPC, dramatize the virtue of bimodal killing by a single therapeutic agent, and suggest a therapeutic strategy for killing tumor cells that overexpress Myc while sparing normal cells.

Original languageEnglish (US)
Pages (from-to)13836-13841
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number31
DOIs
StatePublished - Aug 3 2010

Keywords

  • Apoptosis
  • Aurora kinase
  • Autophagy synthetic lethality
  • Chromosomal passenger protein complex
  • Targeted therapy

ASJC Scopus subject areas

  • General

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