Potentiation of Carboplatin-Mediated DNA Damage by the Mdm2 Modulator Nutlin-3a in a Humanized Orthotopic Breast-to-Lung Metastatic Model.

Abstract

Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein-protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC.

• Authors: Eva Tonsing-Carter, Barbara J Bailey, M Reza Saadatzadeh, Jixin Ding, Haiyan Wang, Anthony L Sinn, Kacie M Peterman, Tiaishia K Spragins, Jayne M Silver, Alyssa A Sprouse, Taxiarchis M Georgiadis, T Zachary Gunter, Eric C Long, Robert E Minto, Christophe C Marchal, Christopher N Batuello, Ahmad R Safa, Helmut Hanenberg, Paul R Territo, George E Sandusky, Lindsey D Mayo, Christine M Eischen, Harlan E Shannon, Karen E Pollok
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 12 Pg. 2850-63 (Dec 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 26494859 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• DNA-Binding Proteins
• H2AX protein, human
• Histones
• Imidazoles
• Nuclear Proteins
• Piperazines
• TP53 protein, human
• Trp73 protein, mouse
• Tumor Protein p73
• Tumor Suppressor Protein p53
• Tumor Suppressor Proteins
• nutlin 3
• Carboplatin
• Mdm2 protein, mouse
• Proto-Oncogene Proteins c-mdm2

Topics

• Animals
• Carboplatin (administration & dosage)
• Cell Death (drug effects, genetics)
• Clinical Trials as Topic
• DNA Damage (drug effects)
• DNA-Binding Proteins (genetics)
• Disease Models, Animal
• Histones (biosynthesis)
• Humans
• Imidazoles (administration & dosage)
• Lung Neoplasms (drug therapy, genetics, pathology, secondary)
• MCF-7 Cells
• Mice
• Neoplasm Metastasis
• Nuclear Proteins (genetics)
• Piperazines (administration & dosage)
• Proto-Oncogene Proteins c-mdm2 (genetics)
• Triple Negative Breast Neoplasms (drug therapy, genetics, pathology)
• Tumor Protein p73
• Tumor Suppressor Protein p53 (genetics)
• Tumor Suppressor Proteins (genetics)