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

Anastasia A. Ionkina, John J. Tentler, Jihye Kim, Anna Capasso, Todd M. Pitts, Karen A. Ryall, Rebekah R. Howison, Peter Kabos, Carol A. Sartorius, Aik-Choon Tan, S. Gail Eckhardt, Jennifer R. Diamond

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article number94
JournalFrontiers in Oncology
Volume7
Issue numberMAY
DOIs
Publication statusPublished - 2017 May 15
Externally publishedYes

Fingerprint

Aurora Kinases
Triple Negative Breast Neoplasms
Angiogenesis Inhibitors
Heterografts
Therapeutics
Apoptosis
ENMD 2076
Androgen Receptors
Research Design
Clinical Trials

Keywords

  • Aurora kinase A
  • ENMD-2076
  • Resistance mechanisms
  • Senescence
  • Targeted therapy
  • Triple negative breast cancer

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Ionkina, Anastasia A.; Tentler, John J.; Kim, Jihye; Capasso, Anna; Pitts, Todd M.; Ryall, Karen A.; Howison, Rebekah R.; Kabos, Peter; Sartorius, Carol A.; Tan, Aik-Choon; Eckhardt, S. Gail; Diamond, Jennifer R.

In: Frontiers in Oncology, Vol. 7, No. MAY, 94, 15.05.2017.

Research output: Contribution to journalArticle

Ionkina, AA, Tentler, JJ, Kim, J, Capasso, A, Pitts, TM, Ryall, KA, Howison, RR, Kabos, P, Sartorius, CA, Tan, A-C, Eckhardt, SG & Diamond, JR 2017, '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', Frontiers in Oncology, vol. 7, no. MAY, 94. https://doi.org/10.3389/fonc.2017.00094
Ionkina, Anastasia A. ; Tentler, John J. ; Kim, Jihye ; Capasso, Anna ; Pitts, Todd M. ; Ryall, Karen A. ; Howison, Rebekah R. ; Kabos, Peter ; Sartorius, Carol A. ; Tan, Aik-Choon ; Eckhardt, S. Gail ; Diamond, Jennifer R. / 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. In: Frontiers in Oncology. 2017 ; Vol. 7, No. MAY.
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AU - Kim, Jihye

AU - Capasso, Anna

AU - Pitts, Todd M.

AU - Ryall, Karen A.

AU - Howison, Rebekah R.

AU - Kabos, Peter

AU - Sartorius, Carol A.

AU - Tan, Aik-Choon

AU - Eckhardt, S. Gail

AU - Diamond, Jennifer R.

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