Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase.
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.
Yang
Dun
D
Department of Microbiology and Immunology, G. W. Hooper Research Foundation, University of California, San Francisco, CA 94143, USA.
Liu
Hong
H
Goga
Andrei
A
Kim
Suwon
S
Yuneva
Mariia
M
Bishop
J Michael
JM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001343:Autophagy / Q000187:drug effects; D048749:Cytokinesis; D004261:DNA Replication; D004195:Disease Models, Animal; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008854:Microscopy, Electron; D009368:Neoplasm Transplantation; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D064107:Aurora Kinase B; D064127:Aurora Kinases; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; C000715470:MAS1 protein, human; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; C576925:Aurkb protein, rat