Aurora a kinase inhibition selectively synergizes with histone deacetylase inhibitor through cytokinesis failure in T-cell lymphoma

Kelly M. Zullo, Yige Guo, Laurence Cooke, Xavier Jirau-Serrano, Michael Mangone, Luigi Scotto, Jennifer E. Amengual, Yinghui Mao, Renu Nandakumar, Serge Cremers, Jimmy Duong, Daruka Mahadevan, Owen A. O'Connor

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Purpose: Aurora A kinase (AAK) is expressed exclusively during mitosis, and plays a critical role in centrosome duplication and spindle formation. Alisertib is a highly selective AAK inhibitor that has demonstrated marked clinical activity of alisertib across a spectrum of lymphomas, though particularly in patients with T-cell lymphoma (TCL). We sought to compare and contrast the activity of alisertib in preclinical models of B-cell lymphoma (BCL) and TCL, and identify combinations worthy of clinical study. High-throughput screening of prala-trexate, the proteasome inhibitor (ixazomib), and the histone deacetylase (HDAC) inhibitor (romidepsin) revealed that only romidepsin synergized with alisertib, and only in models of TCL. We discovered that the mechanism of synergy between AAK inhibitors and HDAC inhibitors appears to be mediated through cytokinesis failure. Experimental Design: A high-throughput screening approach was used to identify drugs that were potentially synergistic in combination with alisertib. Live-cell imaging was used to explore the mechanistic basis for the drug: drug interaction between alisertib and romidepsin. An in vivo xenograft TCL model was used to confirm in vitro results. Results: In vitro, alisertib exhibited concentration-dependent cytotoxicity in BCL and TCL cell lines. Alisertib was synergistic with romidepsin in a T-cell-specific fashion that was confirmed in vivo. Live-cell imaging demonstrated that the combination treatment resulted in profound cytokinesis failure. Conclusions: These data strongly suggest that the combination of alisertib and romidepsin is highly synergistic in TCL through modulation of cytokinesis and merits clinical development.

Original languageEnglish (US)
Pages (from-to)4097-4109
Number of pages13
JournalClinical Cancer Research
Volume21
Issue number18
DOIs
StatePublished - Sep 15 2015

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Aurora Kinases
Histone Deacetylase Inhibitors
Cytokinesis
T-Cell Lymphoma
Aurora Kinase A
B-Cell Lymphoma
MLN 8237
Centrosome
Proteasome Inhibitors
Drug Interactions
Mitosis
Heterografts
Pharmaceutical Preparations
Lymphoma
Research Design
romidepsin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Aurora a kinase inhibition selectively synergizes with histone deacetylase inhibitor through cytokinesis failure in T-cell lymphoma. / Zullo, Kelly M.; Guo, Yige; Cooke, Laurence; Jirau-Serrano, Xavier; Mangone, Michael; Scotto, Luigi; Amengual, Jennifer E.; Mao, Yinghui; Nandakumar, Renu; Cremers, Serge; Duong, Jimmy; Mahadevan, Daruka; O'Connor, Owen A.

In: Clinical Cancer Research, Vol. 21, No. 18, 15.09.2015, p. 4097-4109.

Research output: Contribution to journalArticle

Zullo, KM, Guo, Y, Cooke, L, Jirau-Serrano, X, Mangone, M, Scotto, L, Amengual, JE, Mao, Y, Nandakumar, R, Cremers, S, Duong, J, Mahadevan, D & O'Connor, OA 2015, 'Aurora a kinase inhibition selectively synergizes with histone deacetylase inhibitor through cytokinesis failure in T-cell lymphoma', Clinical Cancer Research, vol. 21, no. 18, pp. 4097-4109. https://doi.org/10.1158/1078-0432.CCR-15-0033
Zullo, Kelly M. ; Guo, Yige ; Cooke, Laurence ; Jirau-Serrano, Xavier ; Mangone, Michael ; Scotto, Luigi ; Amengual, Jennifer E. ; Mao, Yinghui ; Nandakumar, Renu ; Cremers, Serge ; Duong, Jimmy ; Mahadevan, Daruka ; O'Connor, Owen A. / Aurora a kinase inhibition selectively synergizes with histone deacetylase inhibitor through cytokinesis failure in T-cell lymphoma. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 18. pp. 4097-4109.
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T1 - Aurora a kinase inhibition selectively synergizes with histone deacetylase inhibitor through cytokinesis failure in T-cell lymphoma

AU - Zullo, Kelly M.

AU - Guo, Yige

AU - Cooke, Laurence

AU - Jirau-Serrano, Xavier

AU - Mangone, Michael

AU - Scotto, Luigi

AU - Amengual, Jennifer E.

AU - Mao, Yinghui

AU - Nandakumar, Renu

AU - Cremers, Serge

AU - Duong, Jimmy

AU - Mahadevan, Daruka

AU - O'Connor, Owen A.

PY - 2015/9/15

Y1 - 2015/9/15

N2 - Purpose: Aurora A kinase (AAK) is expressed exclusively during mitosis, and plays a critical role in centrosome duplication and spindle formation. Alisertib is a highly selective AAK inhibitor that has demonstrated marked clinical activity of alisertib across a spectrum of lymphomas, though particularly in patients with T-cell lymphoma (TCL). We sought to compare and contrast the activity of alisertib in preclinical models of B-cell lymphoma (BCL) and TCL, and identify combinations worthy of clinical study. High-throughput screening of prala-trexate, the proteasome inhibitor (ixazomib), and the histone deacetylase (HDAC) inhibitor (romidepsin) revealed that only romidepsin synergized with alisertib, and only in models of TCL. We discovered that the mechanism of synergy between AAK inhibitors and HDAC inhibitors appears to be mediated through cytokinesis failure. Experimental Design: A high-throughput screening approach was used to identify drugs that were potentially synergistic in combination with alisertib. Live-cell imaging was used to explore the mechanistic basis for the drug: drug interaction between alisertib and romidepsin. An in vivo xenograft TCL model was used to confirm in vitro results. Results: In vitro, alisertib exhibited concentration-dependent cytotoxicity in BCL and TCL cell lines. Alisertib was synergistic with romidepsin in a T-cell-specific fashion that was confirmed in vivo. Live-cell imaging demonstrated that the combination treatment resulted in profound cytokinesis failure. Conclusions: These data strongly suggest that the combination of alisertib and romidepsin is highly synergistic in TCL through modulation of cytokinesis and merits clinical development.

AB - Purpose: Aurora A kinase (AAK) is expressed exclusively during mitosis, and plays a critical role in centrosome duplication and spindle formation. Alisertib is a highly selective AAK inhibitor that has demonstrated marked clinical activity of alisertib across a spectrum of lymphomas, though particularly in patients with T-cell lymphoma (TCL). We sought to compare and contrast the activity of alisertib in preclinical models of B-cell lymphoma (BCL) and TCL, and identify combinations worthy of clinical study. High-throughput screening of prala-trexate, the proteasome inhibitor (ixazomib), and the histone deacetylase (HDAC) inhibitor (romidepsin) revealed that only romidepsin synergized with alisertib, and only in models of TCL. We discovered that the mechanism of synergy between AAK inhibitors and HDAC inhibitors appears to be mediated through cytokinesis failure. Experimental Design: A high-throughput screening approach was used to identify drugs that were potentially synergistic in combination with alisertib. Live-cell imaging was used to explore the mechanistic basis for the drug: drug interaction between alisertib and romidepsin. An in vivo xenograft TCL model was used to confirm in vitro results. Results: In vitro, alisertib exhibited concentration-dependent cytotoxicity in BCL and TCL cell lines. Alisertib was synergistic with romidepsin in a T-cell-specific fashion that was confirmed in vivo. Live-cell imaging demonstrated that the combination treatment resulted in profound cytokinesis failure. Conclusions: These data strongly suggest that the combination of alisertib and romidepsin is highly synergistic in TCL through modulation of cytokinesis and merits clinical development.

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JO - Clinical Cancer Research

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