Combining an Aurora Kinase Inhibitor and a Death Receptor Ligand/Agonist Antibody Triggers Apoptosis in Melanoma Cells and Prevents Tumor Growth in Preclinical Mouse Models.

Abstract

PURPOSE:

Preclinical studies show that inhibition of aurora kinases in melanoma tumors induces senescence and reduces tumor growth, but does not cause tumor regression. Additional preclinical models are needed to identify agents that will synergize with aurora kinase inhibitors to induce tumor regression.

EXPERIMENTAL DESIGN:

We combined treatment with an aurora kinase A inhibitor, MLN8237, with agents that activate death receptors (Apo2L/TRAIL or death receptor 5 agonists) and monitored the ability of this treatment to induce tumor apoptosis and melanoma tumor regression using human cell lines and patient-derived xenograft (PDX) mouse models.

RESULTS:

We found that this combined treatment led to apoptosis and markedly reduced cell viability. Mechanistic analysis showed that the induction of tumor cell senescence in response to the AURKA inhibitor resulted in a decreased display of Apo2L/TRAIL decoy receptors and increased display of one Apo2L/TRAIL receptor (death receptor 5), resulting in enhanced response to death receptor ligand/agonists. When death receptors were activated in senescent tumor cells, both intrinsic and extrinsic apoptotic pathways were induced independent of BRAF, NRAS, or p53 mutation status. Senescent tumor cells exhibited BID-mediated mitochondrial depolarization in response to Apo2L/TRAIL treatment. In addition, senescent tumor cells had a lower apoptotic threshold due to decreased XIAP and survivin expression. Melanoma tumor xenografts of one human cell line and one PDX displayed total blockage of tumor growth when treated with MLN8237 combined with DR5 agonist antibody.

CONCLUSIONS:

These findings provide a strong rationale for combining senescence-inducing therapeutics with death receptor agonists for improved cancer treatment.

• Authors: Yan Liu, Oriana E Hawkins, Anna E Vilgelm, Jeffrey S Pawlikowski, Jeffrey A Ecsedy, Jeffrey A Sosman, Mark C Kelley, Ann Richmond
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 23 Pg. 5338-48 (Dec 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 26152738 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Azepines
• MLN 8237
• Protein Kinase Inhibitors
• Pyrimidines
• Receptors, Death Domain
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Receptors, Tumor Necrosis Factor, Member 10c
• TNF-Related Apoptosis-Inducing Ligand
• Tumor Suppressor Protein p53
• Aurora Kinases
• Caspases

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects, genetics)
• Aurora Kinases (antagonists & inhibitors)
• Azepines (pharmacology)
• Caspases (metabolism)
• Cell Line, Tumor
• Cellular Senescence (drug effects)
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Female
• Humans
• Melanoma (drug therapy, genetics, metabolism, pathology)
• Mice
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Receptors, Death Domain (agonists)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (metabolism)
• Receptors, Tumor Necrosis Factor, Member 10c (metabolism)
• Signal Transduction (drug effects)
• TNF-Related Apoptosis-Inducing Ligand (pharmacology)
• Tumor Suppressor Protein p53 (genetics, metabolism)
• Xenograft Model Antitumor Assays