Efficacy and Molecular Mechanisms of Differentiated Response to the Aurora and Angiogenic Kinase Inhibitor ENMD-2076 in Preclinical Models of p53-Mutated Triple-Negative Breast Cancer
| Autor: | S. Gail Eckhardt, Aik Choon Tan, Carol A. Sartorius, Karen A. Ryall, Anna Capasso, John J. Tentler, Anastasia A. Ionkina, Peter Kabos, Todd M. Pitts, Rebekah R. Howison, Jihye Kim, Jennifer R. Diamond |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Senescence Cancer Research senescence medicine.medical_treatment Phases of clinical research resistance mechanisms Biology aurora kinase A lcsh:RC254-282 Targeted therapy 03 medical and health sciences 0302 clinical medicine Breast cancer medicine Triple-negative breast cancer Original Research Kinase medicine.disease lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens targeted therapy Phenotype 3. Good health 030104 developmental biology Oncology Apoptosis 030220 oncology & carcinogenesis triple negative breast cancer Immunology Cancer research ENMD-2076 |
| Zdroj: | Frontiers in Oncology Frontiers in Oncology, Vol 7 (2017) |
| ISSN: | 2234-943X |
| Popis: | Purpose Triple-negative breast cancer (TNBC) is a subtype associated with poor prognosis and for which there are limited therapeutic options. The purpose of this study was to evaluate the efficacy of ENMD-2076 in p53-mutated TNBC patient-derived xenograft (PDX) models and describe patterns of terminal cell fate in models demonstrating sensitivity, intrinsic resistance, and acquired resistance to ENMD-2076. Experimental design p53-mutated, TNBC PDX models were treated with ENMD-2076 and evaluated for mechanisms of sensitivity or resistance to treatment. Correlative tissue testing was performed on tumor tissue to assess for markers of proliferation, apoptosis, senescence, and pathways of resistance after treatment and at the time of acquired resistance. Results Sensitivity to ENMD-2076 200 mg/kg daily was associated with induction of apoptosis while models exhibiting intrinsic or acquired resistance to treatment presented with a senescent phenotype. Response to ENMD-2076 was accompanied by an increase in p53 and p73 levels, even within the background of mutant p53. Treatment with ENMD-2076 resulted in a decrease in pAurA and an increase in pHH3. We observed a TNBC subtype switch from the luminal androgen receptor to the basal-like subtype at acquired resistance. Conclusion ENMD-2076 has antitumor activity in preclinical models of p53-mutated TNBC. Increased levels of p53 and p73 correlated with sensitivity whereas senescence was associated with resistance to ENMD-2076. The novel finding of a TNBC subtype switch at time of acquired resistance may provide mechanistic insights into the biologic effects of selective pressure of anticancer treatments on TNBC. ENMD-2076 is currently being evaluated in a Phase 2 clinical trial in patients with metastatic, previously treated TNBC where these biologic correlates can be further explored. |
| Databáze: | OpenAIRE |
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