Mdm2 and aurora kinase a inhibitors synergize to block melanoma growth by driving apoptosis and immune clearance of tumor cells.

Vilgelm AE, Pawlikowski JS, Liu Y, Hawkins OE, Davis TA, Smith J, Weller KP, Horton LW, McClain CM, Ayers GD, Turner DC, Essaka DC, Stewart CF, Sosman JA, Kelley MC, Ecsedy JA, Johnston JN, Richmond A
Cancer Res. 2015 75 (1): 181-93

PMID: 25398437 · PMCID: PMC4286469 · DOI:10.1158/0008-5472.CAN-14-2405

Therapeutics that induce cancer cell senescence can block cell proliferation and promote immune rejection. However, the risk of tumor relapse due to senescence escape may remain high due to the long lifespan of senescent cells that are not cleared. Here, we show how combining a senescence-inducing inhibitor of the mitotic kinase Aurora A (AURKA) with an MDM2 antagonist activates p53 in senescent tumors harboring wild-type 53. In the model studied, this effect is accompanied by proliferation arrest, mitochondrial depolarization, apoptosis, and immune clearance of cancer cells by antitumor leukocytes in a manner reliant upon Ccl5, Ccl1, and Cxcl9. The AURKA/MDM2 combination therapy shows adequate bioavailability and low toxicity to the host. Moreover, the prominent response of patient-derived melanoma tumors to coadministered MDM2 and AURKA inhibitors offers a sound rationale for clinical evaluation. Taken together, our work provides a preclinical proof of concept for a combination treatment that leverages both senescence and immune surveillance to therapeutic ends.

©2014 American Association for Cancer Research.

MeSH Terms (17)

Animals Antineoplastic Combined Chemotherapy Protocols Apoptosis Aurora Kinase A Azepines Cell Proliferation Humans Imidazoles Melanoma Melanoma, Experimental Mice, Inbred BALB C Mice, Inbred C57BL Mice, Nude Piperazines Protein Kinase Inhibitors Proto-Oncogene Proteins c-mdm2 Pyrimidines

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