Aurora A Kinase Inhibition Selectively Synergizes with Histone Deacetylase Inhibitor through Cytokinesis Failure in T-cell Lymphoma

Zullo, Kelly; 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.

doi:10.1158/1078-0432.ccr-15-0033

Cited by 42 publications

(32 citation statements)

References 36 publications

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“…LMK-235 displays equipotent HDAC inhibition compared with vorinostat and potent cytotoxicity. In addition, many studies have proposed that HDACis effectively synergize with other diverse anticancer agents that exert antineoplastic effects [14, 15]. Among various synergistic models, the combination of HDACis and the proteasome inhibitor bortezomib has shown undisputed success [16, 17].…”

Section: Introductionmentioning

confidence: 99%

HDAC5, a potential therapeutic target and prognostic biomarker, promotes proliferation, invasion and migration in human breast cancer

Liu

et al. 2016

Oncotarget

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PurposeHistone deacetylase 5 (HDAC5) is an important protein in neural and cardiac diseases and a potential drug target. However, little is known regarding the specific role of HDAC5 in breast cancer (BC). We aimed to evaluate HDAC5 expression in human breast tumors and to determine the effects of the inhibition of HDAC5 expression in BC cells.Experimental designHDAC5 expression was evaluated in BC patients and was correlated with clinical features and with patient prognosis. Functional experiments were performed using shRNA and the selective HDAC inhibitor LMK-235 for HDAC5 knockdown and inhibition in BC cells. The synergistic effects of LMK-235 with the proteasome inhibitor bortezomib were also examined.ResultsHDAC5 was extensively expressed in human BC tissues, and high HDAC5 expression was associated with an inferior prognosis. Knockdown of HDAC5 inhibited cell proliferation, migration, invasion, and enhanced apoptosis. The HDAC5 inhibitor LMK-235 inhibited cell growth and induced apoptosis, while the inclusion of bortezomib synergistically enhanced the efficacy of LMK-235.ConclusionsOur findings indicate that HDAC5 is a promising prognostic marker and drug target for BC and that the combination of LMK-235 and bortezomib presents a novel therapeutic strategy for BC.

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Section: Introductionmentioning

confidence: 99%

HDAC5, a potential therapeutic target and prognostic biomarker, promotes proliferation, invasion and migration in human breast cancer

Liu

et al. 2016

Oncotarget

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“…Zullo et al studied the cytotoxic effects of alisertib in vivo [51]. In addition, the effects of various combination drug regimens involving alisertib in vitro and in vivo on cell lines of r/r TCL were also studied.…”

Section: Preclinical Studies Involving Aurora Kinase Inhibitorsmentioning

confidence: 99%

Novel Aurora Kinase Inhibitor-Based Combination Therapies for PTCL

Tenneti¹,

Davis²,

Mahadevan³

2019

Peripheral T-Cell Lymphomas

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Peripheral T-cell lymphomas (PTCLs) are a rare, heterogeneous group of T-cell non-Hodgkin's lymphomas (T-NHL) that display distinct clinical and biological features. Despite a detailed understanding of PTCL transformation, there is no current accepted standard of care for newly diagnosed or relapsed/refractory (r/r) patients. PTCL are highly proliferative neoplasms with an immunosuppressive microenvironment that elaborates drug resistance to current therapies with poor outcomes. Aurora kinases (AKs) are a family of mitotic oncogenic serine/threonine kinases (A, B/C) that are aberrantly expressed in PTCL, providing a growth advantage. Alisertib, an AK-A inhibitor, blocks the mitotic phase of the cell cycle resulting in apoptosis. Preclinical and clinical trials in PTCL demonstrated an ~30% response rate in r/r PTCL similar to other investigational agents. In order to improve response rates, alisertib-based combination therapies were tested with HDAC inhibitors, romidepsin and vorinostat, in phase Ib trials. To improve response rates to alisertib, we evaluated alisertib-induced polyploidy as a drug resistance mechanism by targeting microtubules with vincristine. In addition, we also targeted immunosuppression-induced proliferation with an anti-PD-L1 antibody and PI3K inhibition in PTCL. Targeting aberrant proliferation and immunosuppression is a novel strategy that warrants evaluation in clinical trials for PTCL, an unmet clinical need.

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“…T‐cell lymphomas are composed of a heterogeneous subset of T‐cell‐derived non‐Hodgkin's lymphomas and show poor prognosis following treatment with the presently available therapeutic options . Therefore, novel treatment strategies are necessary for the improvement of the prognosis of patients with TCLs.…”

Section: Mechanisms Of Action Of Hdac Inhibitors In the Treatment Of mentioning

confidence: 99%

“…Increased AAK expression is found to be related to malignant transformation, especially in TCLs . Alisertib selectively inhibits AAK through its competitive binding to the ATP‐binding site on AAK . Treatment with alisertib perturbs the cell cycle, leading to the accumulation of cells in the G 2 /M phase and the development of polyploidization.…”

Section: Mechanisms Of Action Of Hdac Inhibitors In the Treatment Of mentioning

confidence: 99%

Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies

2016

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Histone deacetylases (HDACs) critically regulate gene expression by determining the acetylation status of histones. Studies have increasingly focused on the activities of HDACs, especially involving non‐histone proteins, and their various biological effects. Aberrant HDAC expression observed in several kinds of human tumors makes HDACs potential targets for cancer treatment. Several preclinical studies have suggested that HDAC inhibitors show some efficacy in the treatment of acute myelogenous leukemia with AML1‐ETO, which mediates transcriptional repression through its interaction with a complex including HDAC1. Recurrent mutations in epigenetic regulators are found in T‐cell lymphomas (TCLs), and HDAC inhibitors and hypomethylating agents were shown to act cooperatively in the treatment of TCLs. Preclinical modeling has suggested that persistent activation of the signal transducer and activator of transcription signaling pathway could serve as a useful biomarker of resistance to HDAC inhibitor in patients with cutaneous TCL. Panobinostat, a pan‐HDAC inhibitor, in combination with bortezomib and dexamethasone, has achieved longer progression‐free survival in patients with relapsed/refractory multiple myeloma (MM) than the placebo in combination with bortezomib and dexamethasone. Panobinostat inhibited MM cell growth by degrading protein phosphatase 3 catalytic subunit α (PPP3CA), a catalytic subunit of calcineurin. This degradation was suggested to be mediated by the blockade of the chaperone function of heat shock protein 90 due to HDAC6 inhibition. Aberrant PPP3CA expression in advanced MM indicated a possible correlation between high PPP3CA expression and the pathogenesis of MM. Furthermore, PPP3CA was suggested as a common target of panobinostat and bortezomib.

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Aurora A Kinase Inhibition Selectively Synergizes with Histone Deacetylase Inhibitor through Cytokinesis Failure in T-cell Lymphoma

Cited by 42 publications

References 36 publications

HDAC5, a potential therapeutic target and prognostic biomarker, promotes proliferation, invasion and migration in human breast cancer

HDAC5, a potential therapeutic target and prognostic biomarker, promotes proliferation, invasion and migration in human breast cancer

Novel Aurora Kinase Inhibitor-Based Combination Therapies for PTCL

Action mechanisms of histone deacetylase inhibitors in the treatment of hematological malignancies

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