p53 Family Members Regulate Phenotypic Response to Aurora Kinase A Inhibition in Triple-Negative Breast Cancer

Tentler, John J.; Ionkina, Anastasia A.; Tan, Aik Choon; Newton, Timothy P.; Pitts, Todd M.; Glogowska, Magdalena J.; Kabos, Peter; Sartorius, Carol A.; Sullivan, Kelly D.; Espinosa, Joaquín M.; Eckhardt, S. Gail; Diamond, Jennifer R.

doi:10.1158/1535-7163.mct-14-0538-t

Cited by 43 publications

(58 citation statements)

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“…In some models, if p53 activity is lost, cells appear to be more sensitive to Aurora kinase A and B inhibition [26]. However in a triple negative breast cancer model, knockdown of wildtype p53 abrogated the alisertib apoptotic activity [15]. Assessment of p53 by immunoblotting in our studies demonstrated an induction of p53 in the sensitive p53 WT HCT116 CRC cell line at all time points, however after 48 hours of treatment with alisertib the induction is more pronounced.…”

Section: Discussionmentioning

confidence: 99%

“…This treatment also resulted in upregulation of p53, p21 and p27. Furthermore, in triple negative breast cancer alisertib demonstrated antiproliferative effects regardless of subtype, however there was a trend whereby increased p53 mRNA expression associated with increased sensitivity to alisertib [15]. In addition, in combination with dexamethasone, doxorubicin, or bortezomib, alisertib induced synergistic./additive activity in vitro [16].…”

Section: Introductionmentioning

confidence: 99%

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Antitumor activity of the aurora a selective kinase inhibitor, alisertib, against preclinical models of colorectal cancer

et al. 2016

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BackgroundThe Aurora kinases are a family of serine/threonine kinases comprised of Aurora A, B, and C which execute critical steps in mitotic and meiotic progression. Alisertib (MLN8237) is an investigational Aurora A selective inhibitor that has demonstrated activity against a wide variety of tumor types in vitro and in vivo, including CRC.ResultsCRC cell lines demonstrated varying sensitivity to alisertib with IC50 values ranging from 0.06 to > 5 umol/L. Following exposure to alisertib we observed a decrease in pAurora A, B and C in four CRC cell lines. We also observed an increase in p53 and p21 in a sensitive p53 wildtype cell line in contrast to the p53 mutant cell line or the resistant cell lines. The addition of alisertib to standard CRC treatments demonstrated improvement over single agent arms; however, the benefit was largely less than additive, but not antagonistic.MethodsForty-seven CRC cell lines were exposed to alisertib and IC50s were calculated. Twenty-one PDX models were treated with alisertib and the Tumor Growth Inhibition Index was assessed. Additionally, 5 KRAS wildtype and mutant PDX models were treated with alisertib as single agent or in combination with cetuximab or irinotecan, respectively.ConclusionAlisertib demonstrated anti-proliferative effects against CRC cell lines and PDX models. Our data suggest that the addition of alisertib to standard therapies in colorectal cancer if pursued clinically, will require further investigation of patient selection strategies and these combinations may facilitate future clinical studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antitumor activity of the aurora a selective kinase inhibitor, alisertib, against preclinical models of colorectal cancer

et al. 2016

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“…Independent of cell cycle checkpoints, we also sought to determine whether senescence causes resistance to KW-2450 in TNBC cells, as reported by others (28, 29). We did not see significant senescence induction in any TNBC cells treated with 0.5 μM KW-2450 for 5 days; however, we did see induction of senescence at higher concentrations (1, 4 μM) and with longer exposure to KW-2450 (for 10 days) (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 96%

Antitumor Activity of KW-2450 against Triple-Negative Breast Cancer by Inhibiting Aurora A and B Kinases

Kai

Kondo

Wang

et al. 2015

Molecular Cancer Therapeutics

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Currently, no targeted drug is available for triple-negative breast cancer (TNBC), an aggressive breast cancer that does not express estrogen receptor, progesterone receptor, or HER2. TNBC has high mitotic activity, and since Aurora A and B mitotic kinases drive cell division and are overexpressed in tumors with a high mitotic index, we hypothesized that inhibiting Aurora A and B produces a significant antitumor effect in TNBC. We tested this hypothesis by determining the antitumor effects of KW-2450, a multikinase inhibitor of both Aurora A and B kinases. We observed significant inhibitory activities of KW-2450 on cell viability, apoptosis, colony formation in agar, and mammosphere formation in TNBC cells. The growth of TNBC xenografts was significantly inhibited with KW-2450. In cell cycle analysis, KW-2450 induced tetraploid accumulation followed by apoptosis or surviving octaploid (8N) cells, depending on dose. These phenotypes resembled those of Aurora B knockdown and complete pharmaceutical inhibition of Aurora A. We demonstrated that 8N cells resulting from KW-2450 treatment depended on the activation of mitogen-activated protein kinase kinase (MEK) for their survival. When treated with the MEK inhibitor selumetinib combined with KW-2450, compared with KW-2450 alone, the 8N cell population was significantly reduced and apoptosis was increased. Indeed this combination showed synergistic antitumor effect in SUM149 TNBC xenografts. Collectively, Aurora A and B inhibition had a significant antitumor effect against TNBC, and this antitumor effect was maximized by the combination of selumetinib with Aurora A and B inhibition.

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“…Another report shows that triple‐negative breast cancer cells with a mutation in p53 and increased p53 expression are more sensitive than other breast cancer cell lines to ENMD‐2076, another Aurora‐A inhibitior . Consistently, induction of apoptosis in response to MLN8237 exposure is dependent on activity of the p53 family . In addition, the latelet‐activating factor acetylhydrolase and GTP‐binding nuclear protein Ran contribute to development of resistance to Aurora‐A/B inhibitor ZM447439 related to p53 in HCT116 colon cancer cells .…”

Section: Targeting Aurora‐a Kinasementioning

confidence: 82%

Aurora‐A Kinase: A Potent Oncogene and Target for Cancer Therapy

Yan

Wang

et al. 2016

Medicinal Research Reviews

217

181

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The Aurora kinase family comprises three serine/threonine kinases, Aurora-A, -B and -C. Among these, Aurora-A and -B play central roles in mitosis, whereas Aurora-C executes unique roles in meiosis. Overexpression or gene amplification of Aurora kinases have been reported in a broad range of human malignancies, pointing to their role as potent oncogenes in tumorigenesis.Aurora kinases therefore represent promising targets for anticancer therapeutics. So far, a number of Aurora kinase inhibitors (AKIs) have been generated, of which some are currently undergoing clinical trials. Recent studies have unveiled novel unexpected functions of Aurora kinases during cancer development and the mechanisms underlying the anticancer actions of AKIs. In this review, we discuss the most recent advances in Aurora-A kinase research and targeted cancer therapy, focusing on the oncogenic roles and signaling pathways of Aurora-A kinases in contributing tumorigenesis, the recent preclinical and clinical AKI data and potential alternative routes for Aurora-A kinase inhibition.Key words: Aurora-A; Aurora kinase inhibitors (AKIs); targeted cancer therapy; mitosis; tumorigenesis 3 In mammals, the Aurora family of serine/threonine kinases consists of Aurora-A, -B and -C, which share a highly conserved catalytic domain containing auto-phosphorylating sites. The catalytic domain is flanked by a very short C-terminal tail and an N-terminal domain of variable lengths 1,2 . In the C-terminal regions of Auroras, there exists a short amino-acid peptide motif called "destruction box" (D-box). The D-box is recognized by the anaphase-promoting complex/cyclosome (APC/C) for degradation through the ubiquitin/proteasome-dependent pathway ( Fig. 1A). Despite their structural similarities, the expression patterns, cellular localization and physiological functions of these three Aurora kinases are largely distinct.Aurora-A and -B are commonly expressed in most cell types whereas Aurora-C is specially expressed in the testis. Both Aurora-A and -B play key roles in regulating cell-cycle progression from G2 through to cytokinesis. Aurora-C has a unique physiological role in spermatogenesis and functions as a chromosomal passenger protein similar to Aurora-B in mitosis 2 .Overexpression of Aurora-A and -B have been found in multiple types of cancer (Table 1), which function as oncogenes to promote tumorigenesis, providing potential targets for cancer therapy.However, comparatively little information is available regarding the roles of Aurora-C in cancer.In this review, we will focus on recent progress as well as the main unresolved issues associated with Aurora-A in cancer.4 1 FUNCTIONS OF AURORA-A In normal cells a. MitosisIn G1 phase, the level of Aurora-A is rarely detectable. During S phase, a small proportion of Aurora-A is first detected at centrosomes. At late G2 phase, Aurora-A accumulates evidently at centrosomes and becomes activated 3 . During prometaphase and metaphase, active Aurora-A localizes on bipolar spindles and spindle poles after...

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p53 Family Members Regulate Phenotypic Response to Aurora Kinase A Inhibition in Triple-Negative Breast Cancer

Cited by 43 publications

References 51 publications

Antitumor activity of the aurora a selective kinase inhibitor, alisertib, against preclinical models of colorectal cancer

Antitumor activity of the aurora a selective kinase inhibitor, alisertib, against preclinical models of colorectal cancer

Antitumor Activity of KW-2450 against Triple-Negative Breast Cancer by Inhibiting Aurora A and B Kinases

Aurora‐A Kinase: A Potent Oncogene and Target for Cancer Therapy

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