International Journal of Endocrinology

International Journal of Endocrinology / 2014 / Article
Special Issue

Anaplastic Thyroid Carcinoma: Molecular Tools for Diagnosis and Therapy

View this Special Issue

Review Article | Open Access

Volume 2014 |Article ID 816430 |

Enke Baldini, Massimino D’Armiento, Salvatore Ulisse, "A New Aurora in Anaplastic Thyroid Cancer Therapy", International Journal of Endocrinology, vol. 2014, Article ID 816430, 11 pages, 2014.

A New Aurora in Anaplastic Thyroid Cancer Therapy

Academic Editor: Giuliana Salvatore
Received15 Apr 2014
Accepted11 Jun 2014
Published01 Jul 2014


Anaplastic thyroid cancers (ATC) are among the most aggressive human neoplasms with a dire prognosis and a median survival time of few months from the diagnosis. The complete absence of effective therapies for ATC renders the identification of novel therapeutic approaches sorely needed. Chromosomal instability, a feature of all human cancers, is thought to represent a major driving force in thyroid cancer progression and a number of mitotic kinases showing a deregulated expression in malignant thyroid tissues are now held responsible for thyroid tumor aneuploidy. These include the three members of the Aurora family (Aurora-A, Aurora-B, and Aurora-C), serine/threonine kinases that regulate multiple aspects of chromosome segregation and cytokinesis. Over the last few years, several small molecule inhibitors targeting Aurora kinases were developed, which showed promising antitumor effects against a variety of human cancers, including ATC, in preclinical studies. Several of these molecules are now being evaluated in phase I/II clinical trials against advanced solid and hematological malignancies. In the present review we will describe the structure, expression, and mitotic functions of the Aurora kinases, their implications in human cancer progression, with particular regard to ATC, and the effects of their functional inhibition on malignant cell proliferation.

1. Aurora Kinases: From Genes to Proteins

The Aurora kinases belong to a family of serine/threonine kinases having in the Ipl1p (increase in ploidy 1) gene, subsequently named Aurora gene, the founding member discovered in the budding yeast Saccharomyces cerevisiae during a genetic screening for mutations causing defective chromosomal segregation [1]. In yeast, the Ipl1 remains the only Aurora kinase so far identified, while two Aurora kinases have been found in Drosophila melanogaster and in Caenorhabditis elegans [24]. In mammals, three Aurora kinases have been identified and characterized: Aurora-A, Aurora-B, and Aurora-C [5]. The catalytic domains of these three proteins are highly related in sequence, showing 67–76% identity, but their N-terminal domains have little similarity, which is held responsible for their distinct intracellular localizations, substrate specificity, and functions (Figure 1). In addition, the amino acid sequence of the catalytic domains of Aurora-A, Aurora-B, and Aurora-C is highly conserved across different organisms suggesting its relevance for protein functions and regulation mechanisms across species [5]. The expression of all three human Aurora kinases is cell cycle regulated being low in the G1/S phase and maximal in the G2/M phase. In the next three paragraphs, we will briefly summarize our knowledge regarding the characteristics of the Auroras’ encoding genes, their promoter regulation, and protein structure.

1.1. Aurora-A

The Aurora-A is encoded by the AURKA gene (also known as AIK, Aurora/IPL1-like kinase; ARK1, Aurora related kinase 1; AURA, AURORA2; BTAK, breast tumor-amplified kinase; PPP1R47, protein phosphatase 1 regulatory subunit 47; STK15, serine/threonine-protein kinase 15; STK6, serine/threonine kinase 6), located at 20q13.2 and consisting of 11 exons (Gene ID: 6790).

The AURKA promoter contains a putative TATA-box at −37 to −14 and two CCAAT-boxes at −101 to −88 and at −69 to −56 (Eukaryotic Promoter Database, Swiss Institute of Bioinformatics). Tanaka and colleagues analyzed the 1.8 kb 5′-flanking region of the Aurora-A gene and found two distinct cis-regulatory elements: one positively regulates transcription of the Aurora-A gene, while the other is a cell cycle dependent transcriptional repressor [6]. The former is the 7 bp sequence CTTCCGG, located at −85 to −79 and essential for the transcription of the Aurora-A gene, which is bound by the E4TF1, a ubiquitously expressed ETS family protein. The cell cycle dependent transcriptional repressor is formed by tandem repression elements, consisting of a cell cycle dependent element (CDE) located at −44 to −40 (CGCCC) and a cell cycle gene homology region (CHR) located at −39 to −35 (TTAAA) [6]. It is worth mentioning that, in addition to Aurora-A, the G2/M specific transcription of different genes such as cyclin A, cdc25C, cdc2, polo-like kinase, and others is regulated by similar tandem repression elements [69]. Over the last few years, a number of transcription factors capable of modulating the expression of AURKA gene have been identified. These include the p53, the HIF-1, and the INI1/hSSNF5, all reported to negatively regulate the activity of the AURKA promoter [1012]. Conversely, the transcriptional activity of the AURKA promoter has been shown to increase following the interaction with the ΔEGFR/STAT5 complex in glioblastoma cells [13]. Moreover, the oncogene MYCN, a member of the MYC family of basic helix-loop-helix transcription factors, has been described to bind the AURKA promoter either alone or in complex with the DNA methyl binding protein MeCP2 in the neuroblastoma derived cell line Kelly [14]. EWS-Fli1, a fusion gene resulting from the chromosomal translocation (11; 22, q24; q12), encodes a transcriptional activator capable of promoting cellular transformation in Ewing sarcoma cells. Experimental evidence showed that EWS-Fli1 protein upregulates Aurora-A and Aurora-B expression by binding to regulatory ETS-binding sites located at −84 and −71 bp upstream of the transcription initiation sites in both Aurora-A and Aurora-B promoters [15]. Similarly, it has been suggested that activation of the MAPK in pancreatic cancer cells leads to the transcriptional activation of the AURKA and AURKB promoters via ETS2 transcription factors [16].

The 2.4 kb transcript from AURKA gene encodes a protein of 403 amino acids with a predicted molecular mass of 45.8 kDa (Figure 1). Like all Aurora proteins, it is characterized by a C-terminal catalytic domain containing the activation loop. In the latter, an Aurora kinase signature (xRxTxCGTx) is present in which the autophosphorylation of the Thr288 is required for kinase activation [17]. In addition, the Thr288 is positioned within a protein kinase A (PKA) consensus sequence, and in vitro experiments indicated a potential role of PKA in Aurora-A phosphorylation [18, 19]. The phosphatase PP1 has been shown to dephosphorylate and inactivate Aurora-A [19]. The C-terminal located destruction box (D-box), containing the motif RxxLxxG, and the N-terminal A-box/D-box activating domain (DAD), containing the motif RxLxPS, play an essential role in Aurora-A degradation by the anaphase promoting complex/cyclosome- (APC/C-) ubiquitin-proteasome pathway. Aurora-A degradation occurs in late mitosis/early G1 phase, when the D-box is targeted by Fizzy related proteins that transiently interact with the APC, and is hCdh1 dependent [1821]. In the N-terminal region the amino acidic sequence K-E-N, known as KEN motif, is also present, which serves as targeting signal for Cdh1-APC required also for the degradation of other mitotic proteins such as Nek2 and B99 [22]. However, this does not seem to be crucial for Aurora-A degradation [22].

1.2. Aurora-B

The Aurora-B is encoded by the AURKB gene (also known as AIK2; AIM1; ARK2; AurB; IPL1; STK5; AIM-1; STK12), mapped to chromosome 17p13.1, and consisting of 9 exons (Gene ID: 9212).

The AURKB promoter contains three putative CAAT-boxes at −99 to −86, at −66 to −53, and at −30 to −17 (Eukaryotic Promoter Database, Swiss Institute of Bioinformatics). By primer extension two major transcription initiation sites were identified [23]. As for the Aurora-A promoter, also the Aurora-B promoter possesses the CDE and CHR elements, though responsible for the cell cycle regulation of its expression, and several CDE-binding proteins have been identified by means of electrophoretic mobility shift assay and biotin-streptavidin pull-down assay, including the E2F-1, E2F-4, and DP-2 [23]. As above described, the AURKB promoter may be positively regulated by transcription factors such as the ETS2 via ETS-binding sites present in the promoter sequence [15, 16].

The 1.4 kb transcript encodes a protein of 345 amino acids with a predicted molecular mass of 39 kDa (Figure 1) [5]. As described for Aurora-A, also the Aurora-B protein is characterized by a catalytic domain, a C-terminal D-box, and an N-terminal A-box/DAD [1821]. However, although Aurora-B possesses the same D-box as Aurora-A, it is not degraded by the same ubiquitin ligase but undergoes degradation following its binding to the human proteasome α-subunit C8 in a proteasome dependent manner [24].

1.3. Aurora-C

The Aurora-C is encoded by the AURKC gene (also known as AIE2; AIK3; ARK3; AurC; SPGF5; STK13), which localizes at chromosome 19q13.43 and consists of 7 exons (Gene ID: 6795).

The AURKC promoter contains a CCAAT-box at −36 to −23 (Eukaryotic Promoter Database, Swiss Institute of Bioinformatics). Expression of AURKC is downregulated by PLZF, a transcriptional repressor, through recruitment to its promoter region, and it is of interest to note that the expression levels of PLZF and AURKC mRNAs display opposite patterns in human cervical and colorectal cancers [25].

The 1.3 kb transcript encodes a protein of 309 amino acids with a predicted molecular mass of 35.6 kDa (Figure 1) [5]. As the other members of the family, also Aurora-C is characterized by a catalytic domain present in the C-terminal region of the molecule (Figure 1). However, differently from Aurora-A and Aurora-B, Aurora-C does not contain the KEN and the A-box/DAD motifs in its N-terminal region, while the C-terminal D-box is present. The mechanism(s) underlying its degradation, however, still remains to be elucidated and represents an interesting area of investigation.

2. Expression, Subcellular Localization, and Functions of the Aurora Kinases

The three Aurora kinases play relevant functions during the mitotic phase of the cell cycle [18, 19]. As mentioned, these proteins display distinct intracellular localizations, substrate specificity, and functions during mitosis and their expression and activity are tightly regulated at the transcriptional or posttranscriptional level, through phosphorylation/dephosphorylation and protein degradation [26]. In the next paragraphs, we will briefly discuss the main mitotic functions of the Aurora kinases and we will mention recent reports suggesting their extramitotic functions.

2.1. Aurora-A

The expression of Aurora-A is cell cycle regulated, being very low during the G1 phase and starting to accumulate at the centrosome in the late S phase to be maximal at the G2-M transition. During mitosis it localizes at the spindle poles to be inactivated and degraded before cytokinesis, as above mentioned [19, 22]. Aurora-A regulates centrosome separation and maturation, cell mitotic entry, and bipolar spindle construction. Centrosome recruitment of Aurora-A is controlled by the Cep192/Spd-2 (centrosome protein of 192 kDa/spindle defective 2) which is also involved in kinase activation during mitosis [27]. Once on the centrosome, Aurora-A promotes the recruitment to the pericentriolar mass (PCM) of a number of proteins required for proper centrosome maturation and function. These include centrosomin, γ-tubulin, LATS2 (large tumor suppressor, homolog 2), TACC3 (transforming acidic coiled coil 3), and NDEL1 (nuclear distribution element-like 1) [19, 22, 28].

While promoting centrosome maturation, Aurora-A activates the CDK1/cyclin B complex allowing the transition of the cell from the G2 to the M phase [2931]. In particular, Aurora-A in association with the G2 induced Bora protein phosphorylates the PLK1 (polo-like kinase 1). Both Aurora-A and PLK1 phosphorylate CDC25B (cell division cycle 25 B), a member of the CDC25 family of phosphatases which activates cyclin dependent kinases by removing two phosphate groups, leading to CDK1/Cyclin B complex activation and finally promoting mitotic entry [19, 2931]. PLK1 facilitates this process also by inactivating the CDK1 inhibitor WEE1 (Figure 2). Inactivation of Aurora-A or Plk1 individually shows no significant effect on Cdk1 activation and entry to mitosis, while their simultaneous inactivation produces a marked delay in both Cdk1 activation and mitotic entry, suggesting that the two kinases have redundant functions [32].

A central role of Aurora-A during mitosis is to support the microtubule-organizer center (MTOC) responsible for the formation of the bipolar spindle. In this context Aurora-A has been shown to form complexes with TACC1 and TACC3, which in turn, by binding to ch-TOG/XMAP215 proteins, stabilize microtubules at the centrosome [3335]. In addition, Aurora-A interacts with and phosphorylates TPX2, which is capable of promoting spindle microtubule polymerization [22].

2.2. Aurora-B

Aurora-B mRNA and protein levels peak at G2/M phase, and the maximum kinase activity is reached from metaphase to the end of mitosis [18, 19]. Aurora-B exerts its action mainly in concert with three other proteins, that is, INCENP (inner centromere protein), survivin, and borealin/Dasra B, with which it associates in the chromosomal passenger complex (CPC). In early prophase, the CPC is located on chromosomal condensing arms where it seems to displace the heterochromatin protein-1 from DNA and to recruit condensin proteins (Figure 3) [36, 37]. From early G2 phase to prophase, Aurora-B phosphorylates histone H3, but its physiological meaning remains unclear. From late prophase to metaphase CPC localizes to the inner centromere, playing a role in formation and stability of the bipolar mitotic spindle, kinetochore assembly, correction of nonbipolar chromosome-spindle attachments, and control of the spindle checkpoint (Figure 3). At the beginning of anaphase CPC relocates to the midzone of the mitotic spindle and to the cell cortex, remaining evident in the midbody of telophasic cells where it modulates the activity of several proteins involved in spindle dynamics, cleavage furrow formation, and completion of cytokinesis (Figure 3) [18, 19, 36, 37].

Aurora-B activation requires its autophosphorylation and binding to INCENP, while all CPC components are necessary for its proper localization during mitosis. Several kinases, such as BubR1 and Bub1 (checkpoint kinases), Mps1 (monopolar spindle 1), Chkl (checkpoint kinase 1), tousled-like kinase-1, Plk1, and TD-60/RCC2 (regulator of chromosome condensation 2), have been recently shown to be involved in Aurora-B activation. TD-60, a protein with a chromosomal passenger-like localization pattern, seems to be also important for centromeric localization of Aurora-B [38]. The phosphorylation status and activity of Aurora-B are modulated by PP1 and PP2A phosphatases; depending on the regulatory subunit they are bound to, these enzymes can directly modulate Aurora-B activity through dephosphorylation or they may dephosphorylate Aurora-B substrates [38].

2.3. Aurora-C

Expression of Aurora-C is maximal during the G2/M phase. The observation that Aurora-C is expressed at relative high levels in germ cells during spermatogenesis and oogenesis and at very low levels in somatic cells is of interest. Aurora-C is highly similar to Aurora-B in sequence (61% identity), which may explain why the two kinases display similar localization patterns and share interacting proteins and substrates such as INCENP, survivin, and borealin [18, 39]. Interestingly, when ectopically expressed in cells depleted of Aurora-B, Aurora-C is capable of rescuing the Aurora-B-dependent mitotic functions [40]. It is also worth noting that Aurora-C has been shown to interact with and phosphorylate TACC1 in thyroid cells [40]. In the latter, TACC1 and Aurora-C have been shown to colocalize in the cytokinetic bridge [41].

2.4. Extramitotic Functions of Aurora Kinases

Over the last few years, different experimental findings suggest extramitotic functions for Aurora-A and Aurora-C. In particular, Aurora-A has been proposed to affect microtubule dynamics, cell migration and polarity, cilia disassembly, and regulation of intracellular calcium signaling in interphasic cells [22]. Regarding Aurora-C, it has been shown that, along with its interacting protein TACC1, it may be involved in telomere stability. In particular, TACC1 has been shown to bind the LSM7 and SmG proteins involved in telomere formation, while the TFR2 protein, a component of the telomeric complex shelterin, has been shown to form a complex with Aurora-C [42, 43]. Thus, it may be speculated that TACC1 and/or Aurora-C may contribute to telomere homeostasis.

3. Aurora Kinases and Cancer

Genetic instability, a hallmark of solid tumors, is thought to represent the mean by which premalignant cells acquire novel functional capabilities responsible for cancer cell growth and tumour progression [44]. In fact, aberrations in chromosome number and structure characterize the majority of human cancers and follow alterations of cellular functions required for appropriate chromosome segregation and integrity of cellular checkpoints [45]. Given the crucial tasks of Aurora kinases in all mitotic stages, their dysfunction and/or dysregulation may well lead to abnormal cell divisions and aneuploidy. However, whether Aurora kinases have a role in cancer initiation is still a matter of debate. It has been reported that the overexpression of either Aurora-A, Aurora-B, or Aurora-C induces cell malignant transformation [4648]. In different studies, however, although the ability of Aurora-A or Aurora-B to potentiate Ras-induced transformation was demonstrated, the transforming ability of either Aurora-A or Aurora-B overexpression alone was not observed [49, 50].

Aurora-A kinase has been often implicated in cancer progression and its hyperactivation has been demonstrated to induce resistance to microtubule-targeted chemotherapy [5153]. The AURKA gene is often amplified in many malignancies, and its overexpression has been reported to be significantly associated with a higher tumor grade and a poor prognosis in a number of cancers, such as chondrosarcoma, nasopharyngeal carcinoma, ER-positive breast cancer, glioblastoma, colorectal cancer, gastric cancer, and endometrioid ovarian carcinoma [5460]. In addition, somatic mutations located within the catalytic domain of Aurora-A, altering kinase activity and subcellular localization, have been described in human cancer cells [61]. The oncogenic potential of Aurora-A derives from a sum of several spatially and temporally distinct actions. Unlike normal cells, in many cancer cells the expression of Aurora-A becomes constitutive throughout the cytoplasm, regardless of the cell cycle phase; this can trigger a plethora of phosphorylated proteins, improper interactions, and mislocalization. Aurora-A may also represent the downstream target of mitogenic pathways, such as MAPK/ERK (mitogen-activated protein kinases), and hence be overexpressed because of their constitutive activation in tumors [52]. The Aurora-A excess interferes with different cell cycle checkpoints, that is, the late G2 checkpoint, which restrains genetically aberrant cells to enter mitosis, the spindle assembly checkpoint, which blocks the metaphase-anaphase transition in cells with defective spindles, and the postmitotic G1 checkpoint, which arrests cell cycle in aneuploid cells [51, 53]. Centrosome amplification and unrestrained multinucleation, leading to abnormal mitotic spindle, are also observed in Aurora-A overexpressing cells [62]. Moreover, Aurora-A may significantly contribute to tumor progression by interacting with and inhibiting several tumor suppressor proteins such as p53, BRCA1 (breast cancer 1), and Chfr (checkpoint with forkhead and ring finger domains).

Aurora-B plays a less clear role in tumorigenesis. An increased level of Aurora-B in normal cells has been shown to induce premature chromosome separation and segregation errors, to promote generation of tetraploid and aneuploid cells, which develop a transformed phenotype in vitro and in vivo, and, as above mentioned, to potentiate Ras oncogenic activity [47, 50, 6365]. Neither amplification nor specific mutations of its gene have been shown in tumors; nevertheless, Aurora-B overexpression has been demonstrated in several cancer types, like breast, colorectal, kidney, lung, and prostate cancer, and it has been reported to correlate with the level of genomic instability and with poor prognosis in advanced colorectal cancer, astrocytoma, head and neck squamous cell cancer, and endometrial and hepatocellular carcinomas [51, 6365]. At present, very little information is available about the role of Aurora-C in cancers. Despite Aurora-C is hardly detected in normal somatic cells, it is highly expressed in various tumor cell lines [6669]. One study has described the transforming potential of overexpressed Aurora-C in NIH-3T3 cells and a correlation between the level of active kinase and tumor aggressiveness of the cells injected in nude mice [48].

The overexpression of Aurora kinases in human cancers and their relevance in controlling the mitotic process have led to the development of small-molecule inhibitors as putative anticancer drugs. Aurora inhibition results in cytokinesis failure and generation of tetraploid cells, which, depending on the postmitotic checkpoint activation, may be unable to proceed in cell cycle or rather proliferate and become polyploid. The exit from cell cycle is likely to generate viable quiescent cells, whereas endoreplicating cells have greater tendency to undergo apoptosis. Nowadays the Aurora kinase inhibitors are considered a promising therapeutic option, especially against those cancers that do not respond to currently available anticancer therapies [7077]. About 30 small molecule inhibitors of Aurora kinases are under preclinical and clinical evaluation with some of them, reported in Table 1, undergoing phase I-II clinical trials for solid and hematological cancers [7077]. The responses obtained in these clinical trials showed either disease stabilization or less frequently partial responses in patients with solid cancers, while more promising activity has been observed in patients with hematological malignancies [7077]. However, a number of side effects, most of which reversible upon drug withdrawal, were observed [74]. On-target toxicity encountered in the different clinical trials included grade 3/4 neutropenia, leukopenia, and myelosuppression, while off-target effects included hypertension, somnolence, mucositis, stomatitis, proctalgia, grade 3 increase in aspartate aminotransferase, and ventricular dysfunction [7077]. Cardiotoxicity, associated with death of one patient, has been recorded in a phase II clinical trial with tozasertib (VX-680) [74].

Inhibitor (company) commercial nameClinical trial

Pan-Aurora inhibitorsVX-680/MK-0457 (Vertex/Merck) TozasertibPhase II (terminated due to severe toxicity)
PHA-739358 (Pfizer/Nerviano) DanusertibPhase II
PHA-680632 (Pfizer/Nerviano)Phase II
CYC-116 (Cyclacel)Phase I
SNS-314 (Sunesis)Phase I
R763 (Rigel)Phase I
AMG-900 (Amgen)Phase I
AT-9283 (Astex)Phase II
PF-03814375 (Pfizer)Phase I
GSK1070916 (GlaxoSmithKline)Phase I

Aurora-A inhibitorsMLN8237 (Millennium)Phase II
EMD-2076 (EntreMed)Phase II
MK-5108 (Vertex)Phase I

Aurora-B inhibitorsAZD1152 (AstraZeneca)Phase II

4. Thyroid Cancers

Epithelial thyroid cancer (TC) accounts for about 1% of all human tumors and represents the most common endocrine malignancy, the fifth most common cancer in women in the United States [78, 79]. The majority of TC (90–95%) is differentiated carcinomas (DTC), occurring as papillary (PTC) or follicular (FTC) histotypes, the incidence of which has been increasing over recent years [80]. Following dedifferentiation DTC are assumed to generate the poorly DTC (PDTC) and the highly aggressive and invariably fatal anaplastic thyroid carcinomas (ATC) [81, 82]. Relevant molecular alterations encountered in DTC progression comprise gene rearrangements of tyrosine kinase receptors, such as the RET/PTC and NTRK1 (neurotrophic receptor-tyrosine kinase 1), or activating point mutations of proteins mediating cellular responses to growth and differentiation signals, including RAS, BRAF, phosphatidylinositol 3-kinase (PI3K), or the oncogenic fusion protein PAX8-PPARγ, as well as inactivating mutations in the tumor suppressor phosphatase and tensin homolog (PTEN) and TP53 [8385]. The conversion of early-stage thyroid tumors to more aggressive and invasive malignancies occurs through an epithelial-to-mesenchymal transition (EMT), which implies the loss of cell-cell contacts, remodeling of cytoskeleton, and the acquisition of a migratory phenotype [86, 87]. In fact, abnormal expression of integrins, Notch, MET, TGFβ, NF-κB, PI3K, TWIST1, matrix metalloproteinases (MMP), components of the urokinase plasminogen activating system (uPAS), and p21-activated kinase (Pak), involved in the EMT, has been identified in PTC progression [8691]. Genomic instability, a hallmark of solid tumors including TC, is thought to represent the driving force responsible for the generation and accumulation in the malignant cells of the above-mentioned molecular alterations [44, 9294]. According to this, hypothesis is the evidence that the number and the frequency of chromosomal abnormalities, observed during thyroid cancer progression, increase from the DTC to the PDTC and ATC [9294].

While the prognosis for DTC patients is favorable, with 10-year survival rate of about 90%, that for patients affected by PDTC and ATC is very poor, with a median survival of only few months from diagnosis [9496]. It has to be noted, in fact, that the surgical resection of the tumor mass is not effective in ATC patients and treatment of recurrent or persistent PDTC and ATC with conventional radiotherapy and/or chemotherapy provides little or no benefit. Therefore, novel therapeutic approaches are sorely needed for these neoplasms [85, 97].

5. Aurora Kinases and Thyroid Cancers

Normal human thyrocytes express all three Aurora kinases in a cell cycle dependent manner [67]. The expression of Aurora-A and Aurora-B in this cell type is mainly regulated at the transcriptional level, while that of Aurora-C appears to be modulated at the posttranscriptional level [67]. An increased expression of all three Aurora kinases has been shown in various cell lines originating from different epithelial thyroid tumor histotypes, compared to normal thyrocytes, as well as in DTC and ATC tissues, compared to normal matched tissues [33, 67, 98]. In addition, a study aimed at evaluating the gene expression profile in ATC, by means of tissue microarray and immunohistochemistry, identified AURKA as one of the most frequently and most strongly overexpressed genes in these tumors [99]. This is consistent with the observation that gain of chromosome 20q, where AURKA is located (20q13.2), is frequently encountered in ATC [100]. Based on these findings, the potential therapeutic value of Aurora kinase inhibition on the proliferation and growth of ATC cells has been evaluated in preclinical studies [101105]. In particular, the in vitro effects of different pan-Aurora kinase inhibitors, including the MK-0457 (VX-680), the SNS-314 mesylate, and the ZM447439, have been investigated on proliferation, apoptosis, cell cycle, ploidy, and anchorage-independent growth of a panel of ATC-derived cell lines [102104]. These molecules were found to inhibit proliferation of ATC cells in a time- and dose-dependent manner and to impair cancer cells colony formation in soft agar. Cytofluorimetric analysis of cell cultures exposed to the pan-Aurora kinase inhibitors revealed an accumulation of tetra- and polyploid cells because of endoreplication events followed by the activation of caspase-3 and accumulation of a sub-G0/G1 cell population, both indicative of apoptosis [102104]. Treated cells showed mitotic alterations consistent with the inhibition of Aurora kinases, including major impairment of centrosome functions, with abnormal spindle formation characterized by the presence of short microtubules, inhibition of histone H3 phosphorylation, and inability to complete the cytokinesis. In addition, the selective inhibition of either Aurora-A or Aurora-B has been investigated [101, 105, 106]. The selective inhibition of Aurora-B expression by means of RNA interference, or of Aurora-B function by AZD1152, has been reported to significantly reduce growth and tumorigenicity of ATC-derived cells, both in vivo and in vitro [101]. Similarly, functional inhibition of Aurora-A by MLN8054 in a panel of ATC-derived cell lines has been shown to inhibit cell proliferation and to induce cell cycle arrest and cell apoptosis [105]. In xenograft experiments, the Aurora-A inhibitor was found to reduce tumor volume by 86% [105]. Interestingly, the combined treatment with MLN8054 and bortezomib, targeting the ubiquitin-proteasome system, showed additive effects on ATC-derived cell proliferation and apoptosis, compared to monotherapy [106]. Pazopanib, an inhibitor of kinases including the VEGFR (vascular endothelial growth factor receptor) shown to have impressive therapeutic activity in patients affected by radioactive iodine-refractory DTC, was tested in a phase II clinical trial on ATC patients [107, 108]. Despite several pazopanib treated ATC patients showed a transient disease regression, no RECIST (response evaluation criteria in solid tumors) response was obtained [106]. More recently, in a preclinical study on a panel of ATC derived cell lines, pazopanib was found to potentiate the cytotoxic effects of paclitaxel in vitro and in xenograft experiments [109]. The effects of this pazopanib were attributed to an unexpected off-target inhibition of Aurora-A in ATC derived cell lines. In fact, the same results were obtained when combining paclitaxel and MLN8237, a selective Aurora-A inhibitor. In the same study, the authors also showed that the combined administration of pazopanib and paclitaxel attained a marked and durable regression of lung metastasis, in a single ATC patient [109].

In conclusion, the preclinical and clinical data so far available indicate that Aurora kinase inhibitors may have a therapeutic potential for ATC treatment either in monotherapy or, more likely, in combination therapy with anti-microtubule drug.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Authors’ Contribution

Enke Baldini, Massimino D’Armiento, and Salvatore Ulisse contributed to writing the first draft and all of them contributed to the revisions and approved the final version of the paper.


This work was supported by the MIUR Grant PRIN2010/2011 (Protocol no. 2010BX2SNA_002).


  1. C. S. M. Chan and D. Botstein, “Isolation and characterization of chromosome-gain and increase-in-ploidy mutants in yeast,” Genetics, vol. 135, no. 3, pp. 677–691, 1993. View at: Google Scholar
  2. D. M. Glover, M. H. Leibowitz, D. A. McLean, and H. Parry, “Mutations in aurora prevent centrosome separation leading to the formation of monopolar spindles,” Cell, vol. 81, no. 1, pp. 95–105, 1995. View at: Publisher Site | Google Scholar
  3. J. M. Schumacher, N. Ashcroft, P. J. Donovan, and A. Golden, “A highly conserved centrosomal kinase, AIR-1, is required for accurate cell cycle progression and segregation of developmental factors in Caenorhabditis elegans embryos,” Development, vol. 125, no. 22, pp. 4391–4402, 1998. View at: Google Scholar
  4. J. M. Schumacher, A. Golden, and P. J. Donovan, “AIR-2: an Aurora/Ipl1-related protein kinase associated with chromosomes and midbody microtubules is required for polar body extrusion and cytokinesis in Caenorhabditis elegans embryos,” Journal of Cell Biology, vol. 143, no. 6, pp. 1635–1646, 1998. View at: Publisher Site | Google Scholar
  5. J. R. Bischoff and G. D. Plowman, “The Aurora/Ipl1p kinase family: regulators of chromosome segregation and cytokinesis,” Trends in Cell Biology, vol. 9, no. 11, pp. 454–459, 1999. View at: Publisher Site | Google Scholar
  6. M. Tanaka, A. Ueda, H. Kanamori et al., “Cell-cycle-dependent regulation of human aurora A transcription is mediated by periodic repression of E4TF1,” The Journal of Biological Chemistry, vol. 277, no. 12, pp. 10719–10726, 2002. View at: Publisher Site | Google Scholar
  7. J. Zwicker, F. C. Lucibello, L. A. Wolfraim et al., “Cell cycle regulation of the cyclin A, cdc25C and cdc2 genes is based on a common mechanism of transcriptional repression,” The EMBO Journal, vol. 14, no. 18, pp. 4514–4522, 1995. View at: Google Scholar
  8. T. Uchiumi, D. L. Longo, and D. K. Ferris, “Cell cycle regulation of the human polo-like kinase (PLK) promoter,” Journal of Biological Chemistry, vol. 272, no. 14, pp. 9166–9174, 1997. View at: Publisher Site | Google Scholar
  9. R. D. Fontijn, B. Goud, A. Echard et al., “The human kinesin-like protein RB6K is under tight cell cycle control and is essential for cytokinesis,” Molecular and Cellular Biology, vol. 21, no. 8, pp. 2944–2955, 2001. View at: Publisher Site | Google Scholar
  10. F. Nikulenkov, C. Spinnler, H. Li et al., “Insights into p53 transcriptional function via genome-wide chromatin occupancy and gene expression analysis,” Cell Death and Differentiation, vol. 19, no. 2, pp. 1992–2002, 2012. View at: Publisher Site | Google Scholar
  11. D. Fanale, V. Bazan, L. R. Corsini et al., “HIF-1 is involved in the negative regulation of AURKA expression in breast cancer cell lines under hypoxic conditions,” Breast Cancer Research and Treatment, vol. 140, no. 3, pp. 505–517, 2013. View at: Publisher Site | Google Scholar
  12. S. Lee, V. Cimica, N. Ramachandra, D. Zagzag, and G. V. Kalpana, “Aurora A is a repressed effector target of the chromatin remodeling protein INI1/hSNF5 required for rhabdoid tumor cell survival,” Cancer Research, vol. 71, no. 9, pp. 3225–3235, 2011. View at: Publisher Site | Google Scholar
  13. K. Latha, M. Li, V. Chumbalkar et al., “Nuclear EGFRvIII-STAT5b complex contributes to glioblastoma cell survival by direct activation of the Bcl-XL promoter,” International Journal of Cancer, vol. 132, no. 3, pp. 509–520, 2013. View at: Publisher Site | Google Scholar
  14. D. M. Murphy, P. G. Buckley, S. Das, K. M. Watters, K. Bryan, and R. L. Stallings, “Co-localization of the oncogenic transcription factor MYCN and the DNA methyl binding protein MeCP2 at genomic sites in neuroblastoma,” PLoS ONE, vol. 6, no. 6, Article ID e21436, 2011. View at: Publisher Site | Google Scholar
  15. K. Wakahara, T. Ohno, M. Kimura et al., “EWS-Fli1 up-regulates expression of the Aurora A and Aurora B kinases,” Molecular Cancer Research, vol. 6, no. 12, pp. 1937–1945, 2008. View at: Publisher Site | Google Scholar
  16. T. Furukawa, N. Kanai, H. O. Shiwaku, N. Soga, A. Uehara, and A. Horii, “AURKA is one of the downstream targets of MAPK1/ERK2 in pancreatic cancer,” Oncogene, vol. 25, no. 35, pp. 4831–4839, 2006. View at: Publisher Site | Google Scholar
  17. T. Marumoto, D. Zhang, and H. Saya, “Aurora-A—a guardian of poles,” Nature Reviews Cancer, vol. 5, no. 1, pp. 42–50, 2005. View at: Publisher Site | Google Scholar
  18. V. M. Bolanos-Garcia, “Aurora kinases,” The International Journal of Biochemistry & Cell Biology, vol. 37, no. 8, pp. 1572–1577, 2005. View at: Publisher Site | Google Scholar
  19. M. Carmena and W. C. Earnshaw, “The cellular geography of Aurora kinases,” Nature Reviews Molecular Cell Biology, vol. 4, no. 11, pp. 842–854, 2003. View at: Publisher Site | Google Scholar
  20. Y. Arlot-Bonnemains, A. Klotzbucher, R. Giet, R. Uzbekov, R. Bihan, and C. Prigent, “Identification of a functional destruction box in the Xenopus laevis aurora-A kinase pEg2,” FEBS Letters, vol. 508, no. 1, pp. 149–152, 2001. View at: Publisher Site | Google Scholar
  21. A. Castro, Y. Arlot-Bonnemains, S. Vigneron, J. C. Labbé, C. Prigent, and T. Lorca, “APC/Fizzy-related targets Aurora—a kinase for proteolysis,” EMBO Reports, vol. 3, no. 5, pp. 457–462, 2002. View at: Publisher Site | Google Scholar
  22. A. S. Nikonova, I. Astsaturov, I. G. Serebriiskii, R. L. Dunbrack Jr., and E. A. Golemis, “Aurora A kinase (AURKA) in normal and pathological cell division,” Cellular and Molecular Life Sciences, vol. 70, no. 4, pp. 661–687, 2013. View at: Publisher Site | Google Scholar
  23. M. Kimura, C. Uchida, Y. Takano, M. Kitagawa, and Y. Okano, “Cell cycle-dependent regulation of the human aurora B promoter,” Biochemical and Biophysical Research Communications, vol. 316, no. 3, pp. 930–936, 2004. View at: Publisher Site | Google Scholar
  24. F. Shu, S. Guo, Y. Dang et al., “Human Aurora-B binds to a proteasome α-subunit HC8 and undergoes degradation in a proteasome-dependent manner,” Molecular and Cellular Biochemistry, vol. 254, no. 1-2, pp. 157–162, 2003. View at: Publisher Site | Google Scholar
  25. J. Tsou, K. Chang, P. Chang-Liao et al., “Aberrantly expressed AURKC enhances the transformation and tumourigenicity of epithelial cells,” Journal of Pathology, vol. 225, no. 2, pp. 243–254, 2011. View at: Publisher Site | Google Scholar
  26. E. Baldini, S. Sorrenti, E. D'Armiento et al., “Aurora kinases: new molecular targets in thyroid cancer therapy,” Clinica Terapeutica, vol. 163, no. 6, pp. e457–e462, 2012. View at: Google Scholar
  27. V. Joukov, A. De Nicolo, A. Rodriguez, J. C. Walter, and D. M. Livingston, “Centrosomal protein of 192 kDa (Cep192) promotes centrosome-driven spindle assembly by engaging in organelle-specific Aurora A activation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 49, pp. 21022–21027, 2010. View at: Publisher Site | Google Scholar
  28. D. Berdnik and J. A. Knoblich, “Drosophila Aurora-A is required for centrosome maturation and actin-dependent asymmetric protein localization during mitosis,” Current Biology, vol. 12, no. 8, pp. 640–647, 2002. View at: Publisher Site | Google Scholar
  29. C. P. C. De Souza, K. A. O. Ellem, and B. G. Gabrielli, “Centrosomal and cytoplasmic Cdc2/cyclin B1 activation precedes nuclear mitotic events,” Experimental Cell Research, vol. 257, no. 1, pp. 11–21, 2000. View at: Publisher Site | Google Scholar
  30. A. Seki, J. A. Coppinger, C. Jang, J. R. Yates III, and G. Fang, “Bora and the kinase Aurora A cooperatively activate the kinase Plk1 and control mitotic entry,” Science, vol. 320, no. 5883, pp. 1655–1658, 2008. View at: Publisher Site | Google Scholar
  31. S. Dutertre, M. Cazales, M. Quaranta et al., “Phosphorylation of CDC25B by Aurora—a at the centrosome contributes to the G2-M transition,” Journal of Cell Science, vol. 117, part 12, pp. 2523–2531, 2004. View at: Publisher Site | Google Scholar
  32. R. D. Van Horn, S. Chu, L. Fan et al., “Cdk1 activity is required for mitotic activation of Aurora A during G2/M transition of human cells,” The Journal of Biological Chemistry, vol. 285, no. 28, pp. 21849–21857, 2010. View at: Publisher Site | Google Scholar
  33. S. Ulisse, E. Baldini, M. Toller et al., “Transforming acidic coiled-coil 3 and Aurora-A interact in human thyrocytes and their expression is deregulated in thyroid cancer tissues,” Endocrine-Related Cancer, vol. 14, no. 3, pp. 827–837, 2007. View at: Publisher Site | Google Scholar
  34. K. Kinoshita, T. L. Noetzel, L. Pelletier et al., “Aurora A phosphorylation of TACC3/maskin is required for centrosome-dependent microtubule assembly in mitosis,” The Journal of Cell Biology, vol. 170, no. 7, pp. 1047–1055, 2005. View at: Publisher Site | Google Scholar
  35. T. P. Barros, K. Kinoshita, A. A. Hyman, and J. W. Raff, “Aurora A activates D-TACC-Msps complexes exclusively at centrosomes to stabilize centrosomal microtubules,” Journal of Cell Biology, vol. 170, no. 7, pp. 1039–1046, 2005. View at: Publisher Site | Google Scholar
  36. S. Ruchaud, M. Carmena, and W. C. Earnshaw, “Chromosomal passengers: conducting cell division,” Nature Reviews Molecular Cell Biology, vol. 8, no. 10, pp. 798–812, 2007. View at: Publisher Site | Google Scholar
  37. G. Vader, R. H. Medema, and S. M. A. Lens, “The chromosomal passenger complex: guiding Aurora-B through mitosis,” The Journal of Cell Biology, vol. 173, no. 6, pp. 833–837, 2006. View at: Publisher Site | Google Scholar
  38. M. S. van der Waal, R. C. C. Hengeveld, A. van der Horst, and S. M. A. Lens, “Cell division control by the Chromosomal Passenger Complex,” Experimental Cell Research, vol. 318, no. 12, pp. 1407–1420, 2012. View at: Publisher Site | Google Scholar
  39. K. Sasai, H. Katayama, D. L. Stenoien et al., “Aurora-C kinase is a novel chromosomal passenger protein that can complement Aurora-B kinase function in mitotic cells,” Cell Motility and the Cytoskeleton, vol. 59, no. 4, pp. 249–263, 2004. View at: Publisher Site | Google Scholar
  40. S. D. Slattery, M. A. Mancini, B. R. Brinkley, and R. M. Hall, “Aurora-C kinase supports mitotic progression in the absence of Aurora-B,” Cell Cycle, vol. 8, no. 18, pp. 2984–2994, 2009. View at: Google Scholar
  41. J. C. Gabillard, S. Ulisse, E. Baldini et al., “Aurora-C interacts with and phosphorylates the transforming acidic coiled-coil 1 protein,” Biochemical and Biophysical Research Communications, vol. 408, no. 4, pp. 647–653, 2011. View at: Publisher Site | Google Scholar
  42. N. Conte, E. Charafe-Jauffret, B. Delaval et al., “Carcinogenesis and translational controls: TACC1 is down-regulated in human cancers and associates with mRNA regulators,” Oncogene, vol. 21, no. 36, pp. 5619–5630, 2002. View at: Publisher Site | Google Scholar
  43. D. Spengler, “The protein kinase Aurora-C phosphorylates TRF2,” Cell Cycle, vol. 6, no. 20, pp. 2579–2580, 2007. View at: Publisher Site | Google Scholar
  44. D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000. View at: Publisher Site | Google Scholar
  45. D. J. Gordon, B. Resio, and D. Pellman, “Causes and consequences of aneuploidy in cancer,” Nature Reviews Genetics, vol. 13, no. 3, pp. 189–203, 2012. View at: Publisher Site | Google Scholar
  46. J. R. Bischoff, L. Anderson, Y. Zhu et al., “A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers,” The EMBO Journal, vol. 17, no. 11, pp. 3052–3065, 1998. View at: Publisher Site | Google Scholar
  47. T. Ota, S. Suto, H. Katayama et al., “Increased mitotic phosphorylation of histone H3 attributable to AIM-1/aurora-B overexpression contributes to chromosome number instability,” Cancer Research, vol. 62, no. 18, pp. 5168–5177, 2002. View at: Google Scholar
  48. J. Khan, F. Ezan, J. Crémet et al., “Overexpression of active Aurora-C kinase results in cell transformation and tumour formation,” PLoS ONE, vol. 6, no. 10, Article ID e26512, 2011. View at: Publisher Site | Google Scholar
  49. M. Tatsuka, S. Sato, S. Kitajima et al., “Overexpression of Aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis,” Oncogene, vol. 24, no. 6, pp. 1122–1127, 2005. View at: Publisher Site | Google Scholar
  50. A. Kanda, H. Kawai, S. Suto et al., “Aurora-B/AIM-1 kinase activity is involved in Ras-mediated cell transformation,” Oncogene, vol. 24, no. 49, pp. 7266–7272, 2005. View at: Publisher Site | Google Scholar
  51. A. A. Dar, L. W. Goff, S. Majid, J. Berlin, and W. El-Rifai, “Aurora kinase inhibitors—rising stars in cancer therapeutics?” Molecular Cancer Therapeutics, vol. 9, no. 2, pp. 268–278, 2010. View at: Publisher Site | Google Scholar
  52. W. Lok, R. Q. Klein, and M. W. Saif, “Aurora kinase inhibitors as anti-cancer therapy,” Anti-Cancer Drugs, vol. 21, no. 4, pp. 339–350, 2010. View at: Publisher Site | Google Scholar
  53. S. Anand, S. Penrhyn-Lowe, and A. R. Venkitaraman, “AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol,” Cancer Cell, vol. 3, no. 1, pp. 51–62, 2003. View at: Publisher Site | Google Scholar
  54. X. Liang, D. Wang, Y. Wang, Z. Zhou, J. Zhang, and J. Li, “Expression of Aurora Kinase A and B in chondrosarcoma and its relationship with the prognosis,” Diagnostic Pathology, vol. 7, no. 1, article 84, 2012. View at: Publisher Site | Google Scholar
  55. Z. G. Liu, W. Yi, Y. L. Tao, H. C. Chan, M. Zeng, and Y. Xia, “Aurora-A is an efficient marker for predicting poor prognosis in human nasopharyngeal carcinoma with aggressive local invasion: 208 cases with a 10-year follow-up from a single institution,” Oncology Letters, vol. 3, no. 6, pp. 1237–1244, 2012. View at: Publisher Site | Google Scholar
  56. H. R. Ali, S.-J. Dawson, F. M. Blows, E. Provenzano, P. D. Pharoah, and C. Caldas, “Aurora kinase A outperforms Ki67 as a prognostic marker in ER-positive breast cancer,” British Journal of Cancer, vol. 106, no. 11, pp. 1798–1806, 2012. View at: Publisher Site | Google Scholar
  57. N. L. Lehman, J. P. O'Donnell, L. J. Whiteley et al., “Aurora A is differentially expressed in gliomas, is associated with patient survival in glioblastoma, and is a potential chemotherapeutic target in gliomas,” Cell Cycle, vol. 11, no. 3, pp. 489–502, 2012. View at: Publisher Site | Google Scholar
  58. E. Dotan, N. J. Meropol, F. Zhu et al., “Relationship of increased aurora kinase A gene copy number, prognosis and response to chemotherapy in patients with metastatic colorectal cancer,” British Journal of Cancer, vol. 106, no. 4, pp. 748–755, 2012. View at: Publisher Site | Google Scholar
  59. J. Wang, S. Yang, H. Zhang et al., “Aurora-A as an independent molecular prognostic marker in gastric cancer,” Oncology Reports, vol. 26, no. 1, pp. 23–32, 2011. View at: Publisher Site | Google Scholar
  60. F. Yang, X. Guo, G. Yang, D. G. Rosen, and J. Liu, “AURKA and BRCA2 expression highly correlate with prognosis of endometrioid ovarian carcinoma,” Modern Pathology, vol. 24, no. 6, pp. 836–845, 2011. View at: Publisher Site | Google Scholar
  61. R. A. Bibby, C. Tang, A. Faisal et al., “A cancer-associated Aurora A mutant is mislocalized and misregulated due to loss of interaction with TPX2,” The Journal of Biological Chemistry, vol. 284, no. 48, pp. 33177–33184, 2009. View at: Publisher Site | Google Scholar
  62. K. B. Lukasiewicz and W. L. Lingle, “Aurora A, centrosome structure, and the centrosome cycle,” Environmental and Molecular Mutagenesis, vol. 50, no. 8, pp. 602–619, 2009. View at: Publisher Site | Google Scholar
  63. H. G. Nguyen, M. Makitalo, D. Yang, D. Chinnappan, C. St. Hilaire, and K. Ravid, “Deregulated Aurora-B induced tetraploidy promotes tumorigenesis,” The FASEB Journal, vol. 23, no. 8, pp. 2741–2748, 2009. View at: Publisher Site | Google Scholar
  64. G. Pannone, S. A. H. Hindi, A. Santoro et al., “Aurora B expression as a prognostic indicator and possibile therapeutic target in oral squamous cell carcinoma,” International Journal of Immunopathology and Pharmacology, vol. 24, no. 1, pp. 79–88, 2011. View at: Google Scholar
  65. Z. Lin, Y. Jeng, F. Hu et al., “Significance of Aurora B overexpression in hepatocellular carcinoma. Aurora B Overexpression in HCC,” BMC Cancer, vol. 10, article 461, 2010. View at: Publisher Site | Google Scholar
  66. M. Kimura, Y. Matsuda, T. Yoshioka, and Y. Okano, “Cell cycle-dependent expression and centrosome localization of a third human Aurora/Ipl1-related protein kinase, AIK3,” The Journal of Biological Chemistry, vol. 274, no. 11, pp. 7334–7340, 1999. View at: Publisher Site | Google Scholar
  67. S. Ulisse, J. Delcros, E. Baldini et al., “Expression of Aurora kinases in human thyroid carcinoma cell lines and tissues,” International Journal of Cancer, vol. 119, no. 2, pp. 275–282, 2006. View at: Publisher Site | Google Scholar
  68. E. Baldini, Y. Arlot-Bonnemains, M. Mottolese et al., “Deregulation of Aurora kinase gene expression in human testicular germ cell tumours,” Andrologia, vol. 42, no. 4, pp. 260–267, 2010. View at: Publisher Site | Google Scholar
  69. E. Baldini, Y. Arlot-Bonnemains, S. Sorrenti et al., “Aurora kinases are expressed in medullary thyroid carcinoma (MTC) and their inhibition suppresses in vitro growth and tumorigenicity of the MTC derived cell line TT,” BMC Cancer, vol. 11, article 411, 2011. View at: Publisher Site | Google Scholar
  70. E. Manchado, M. Guillamot, and M. Malumbres, “Killing cells by targeting mitosis,” Cell Death and Differentiation, vol. 19, no. 3, pp. 369–377, 2012. View at: Publisher Site | Google Scholar
  71. C. H. A. Cheung, M. S. Coumar, J. Y. Chang, and H. P. Hsieh, “Aurora kinase inhibitor patents and agents in clinical testing: an update (2009–10),” Expert Opinion on Therapeutic Patents, vol. 21, no. 6, pp. 857–884, 2011. View at: Publisher Site | Google Scholar
  72. D. Karthigeyan, S. B. B. Prasad, J. Shandilya, S. Agrawal, and T. K. Kundu, “Biology of Aurora A kinase: implications in cancer manifestation and therapy,” Medicinal Research Reviews, vol. 31, no. 5, pp. 757–793, 2011. View at: Publisher Site | Google Scholar
  73. N. Matthews, C. Visintin, B. Hartzoulakis, A. Jarvis, and D. L. Selwood, “Aurora A and B kinases as targets for cancer: will they be selective for tumors?” Expert Review of Anticancer Therapy, vol. 6, no. 1, pp. 109–120, 2006. View at: Publisher Site | Google Scholar
  74. M. Kollareddy, D. Zheleva, P. Dzubak, P. S. Brahmkshatriya, M. Lepsik, and M. Hajduch, “Aurora kinase inhibitors: progress towards the clinic,” Investigational New Drugs, vol. 30, no. 6, pp. 2411–2432, 2012. View at: Publisher Site | Google Scholar
  75. S. Lapenna and A. Giordano, “Cell cycle kinases as therapeutic targets for cancer,” Nature Reviews Drug Discovery, vol. 8, no. 7, pp. 547–566, 2009. View at: Publisher Site | Google Scholar
  76. D. S. Boss, J. H. Beijnen, and J. H. M. Schellens, “Clinical experience with Aurora kinase inhibitors: a review,” Oncologist, vol. 14, no. 8, pp. 780–793, 2009. View at: Publisher Site | Google Scholar
  77. J. J. E. M. Kitzen, M. J. A. de Jonge, and J. Verweij, “Aurora kinase inhibitors,” Critical Reviews in Oncology/Hematology, vol. 73, no. 2, pp. 99–110, 2010. View at: Publisher Site | Google Scholar
  78. S. I. Sherman, “Thyroid carcinoma,” The Lancet, vol. 361, no. 9356, pp. 501–511, 2003. View at: Publisher Site | Google Scholar
  79. A. Jemal, R. Siegel, E. Ward, Y. Hao, J. Xu, and M. J. Thun, “Cancer statistics, 2009,” CA Cancer Journal for Clinicians, vol. 59, no. 4, pp. 225–249, 2009. View at: Publisher Site | Google Scholar
  80. P. Trimboli, S. Ulisse, F. M. Graziano et al., “Trend in thyroid carcinoma size, age at diagnosis, and histology in a retrospective study of 500 cases diagnosed over 20 years,” Thyroid, vol. 16, no. 11, pp. 1151–1155, 2006. View at: Publisher Site | Google Scholar
  81. N. K. Patel and A. R. Shaha, “Poorly differentiated thyroid cancer,” Current Opinion in Otolaryngology & Head & Neck Surgery, vol. 22, no. 2, pp. 121–126, 2014. View at: Publisher Site | Google Scholar
  82. J. L. Pasieka, “Anaplastic thyroid cancer,” Current Opinion in Oncology, vol. 15, no. 1, pp. 78–83, 2003. View at: Publisher Site | Google Scholar
  83. Y. E. Nikiforov, Diagnostic Pathology and Molecular Genetics of the Thyroid, Lippincott Williams & Wilkins, Philadelphia, Pa, USA, 2009.
  84. Y. E. Nikiforov and M. N. Nikiforova, “Molecular genetics and diagnosis of thyroid cancer,” Nature Reviews Endocrinology, vol. 7, no. 10, pp. 569–580, 2011. View at: Publisher Site | Google Scholar
  85. A. Guerra, V. di Crescenzo, and A. Garzi, “Genetic mutations in the treatment of anaplastic thyroid cancer: a systematic review,” BMC Surgery, vol. 13, no. 2, article S44, 2013. View at: Google Scholar
  86. M. A. Huber, N. Kraut, and H. Beug, “Molecular requirements for epithelial-mesenchymal transition during tumor progression,” Current Opinion in Cell Biology, vol. 17, no. 5, pp. 548–558, 2005. View at: Publisher Site | Google Scholar
  87. V. Vasko, A. V. Espinosa, W. Scouten et al., “Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 8, pp. 2803–2808, 2007. View at: Publisher Site | Google Scholar
  88. E. Baldini, M. Toller, F. M. Graziano et al., “Expression of matrix metalloproteinases and their specific inhibitors in normal and different human thyroid tumor cell lines,” Thyroid, vol. 14, no. 11, pp. 881–888, 2004. View at: Publisher Site | Google Scholar
  89. S. Ulisse, E. Baldini, M. Toller et al., “Differential expression of the components of the plasminogen activating system in human thyroid tumour derived cell lines and papillary carcinomas,” European Journal of Cancer, vol. 42, no. 15, pp. 2631–2638, 2006. View at: Publisher Site | Google Scholar
  90. S. Ulisse, E. Baldini, S. Sorrenti et al., “High expression of the urokinase plasminogen activator and its cognate receptor associates with advanced stages and reduced disease-free interval in papillary thyroid carcinoma,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 2, pp. 504–508, 2011. View at: Publisher Site | Google Scholar
  91. S. Ulisse, E. Baldini, S. Sorrenti et al., “In papillary thyroid carcinoma BRAFV600E is associated with increased expression of the urokinase plasminogen activator and its cognate receptor, but not with disease-free interval,” Clinical Endocrinology, vol. 77, no. 5, pp. 780–786, 2012. View at: Publisher Site | Google Scholar
  92. B. Shahedian, Y. Shi, M. Zou, and N. R. Farid, “Thyroid carcinoma is characterized by genomic instability: evidence from p53 mutations,” Molecular Genetics and Metabolism, vol. 72, no. 2, pp. 155–163, 2001. View at: Publisher Site | Google Scholar
  93. V. B. Wreesmann, R. A. Ghossein, S. G. Patel et al., “Genome-wide appraisal of thyroid cancer progression,” American Journal of Pathology, vol. 161, no. 5, pp. 1549–1556, 2002. View at: Publisher Site | Google Scholar
  94. K. N. Patel and A. R. Shaha, “Poorly differentiated and anaplastic thyroid cancer,” Cancer Control, vol. 13, no. 2, pp. 119–128, 2006. View at: Google Scholar
  95. C. Passler, C. Scheuba, G. Prager et al., “Prognostic factors of papillary and follicular thyroid cancer: differences in an iodine-replete endemic goiter region,” Endocrine-Related Cancer, vol. 11, no. 1, pp. 131–139, 2004. View at: Publisher Site | Google Scholar
  96. C. F. A. Eustatia-Rutten, E. P. M. Corssmit, N. R. Biermasz, A. M. Pereira, J. A. Romijn, and J. W. Smit, “Survival and death causes in differentiated thyroid carcinoma,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 1, pp. 313–319, 2006. View at: Publisher Site | Google Scholar
  97. A. Antonelli, P. Fallahi, S. Ulisse et al., “New targeted therapies for anaplastic thyroid cancer,” Anti-Cancer Agents in Medicinal Chemistry, vol. 12, no. 1, pp. 87–93, 2012. View at: Publisher Site | Google Scholar
  98. R. Sorrentino, S. Libertini, P. L. Pallante et al., “Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 2, pp. 928–935, 2005. View at: Publisher Site | Google Scholar
  99. S. M. Wiseman, H. Masoudi, P. Niblock et al., “Anaplastic thyroid carcinoma: Expression profile of targets for therapy offers new insights for disease treatment,” Annals of Surgical Oncology, vol. 14, no. 2, pp. 719–729, 2007. View at: Publisher Site | Google Scholar
  100. R. F. Rodrigues, L. Roque, J. Rosa-Santos, O. Cid, and J. Soares, “Chromosomal imbalances associated with anaplastic transformation of follicular thyroid carcinomas,” British Journal of Cancer, vol. 90, no. 2, pp. 492–496, 2004. View at: Publisher Site | Google Scholar
  101. S. Libertini, A. Abagnale, C. Passaro et al., “AZD1152 negatively affects the growth of anaplastic thyroid carcinoma cells and enhances the effects of oncolytic virus dl922-947,” Endocrine-Related Cancer, vol. 18, no. 1, pp. 129–141, 2011. View at: Publisher Site | Google Scholar
  102. Y. Arlot-Bonnemains, E. Baldini, B. Martin et al., “Effects of the Aurora kinase inhibitor VX-680 on anaplastic thyroid cancer-derived cell lines,” Endocrine-Related Cancer, vol. 15, no. 2, pp. 559–568, 2008. View at: Publisher Site | Google Scholar
  103. E. Baldini, S. Sorrenti, E. D'Armiento et al., “Effects of the Aurora kinases pan-inhibitor SNS-314 mesylate on anaplastic thyroid cancer derived cell lines,” Clinica Terapeutica, vol. 163, no. 5, pp. e307–e313, 2012. View at: Google Scholar
  104. E. Baldini, C. Tuccilli, N. Prinzi et al., “The dual Aurora kinase inhibitor ZM447439 prevents anaplastic thyroid cancer cell growth and tumorigenicity,” Journal of Biological Regulators and Homeostatic Agents, vol. 27, no. 3, pp. 705–715, 2013. View at: Google Scholar
  105. A. Wunderlich, M. Fischer, T. Schloßhauer et al., “Evaluation of Aurora kinase inhibition as a new therapeutic strategy in anaplastic and poorly differentiated follicular thyroid cancer,” Cancer Science, vol. 102, no. 4, pp. 762–768, 2011. View at: Publisher Site | Google Scholar
  106. A. Wunderlich, S. Roth, A. Ramaswamy et al., “Combined inhibition of cellular pathways as a future therapeutic option in fatal anaplastic thyroid cancer,” Endocrine, vol. 42, no. 3, pp. 637–646, 2012. View at: Publisher Site | Google Scholar
  107. K. C. Bible, V. J. Suman, J. R. Molina et al., “Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: results of a phase 2 consortium study,” The Lancet Oncology, vol. 11, no. 10, pp. 962–972, 2010. View at: Publisher Site | Google Scholar
  108. K. C. Bible, V. J. Suman, M. E. Menefee et al., “A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer,” Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 9, pp. 3179–3184, 2012. View at: Publisher Site | Google Scholar
  109. C. R. Isham, A. R. Bossou, V. Negron et al., “Pazopanib enhances paclitaxel-induced mitotic catastrophe in anaplastic thyroid cancer,” Science Translational Medicine, vol. 5, no. 166, p. 166ra3, 2013. View at: Publisher Site | Google Scholar

Copyright © 2014 Enke Baldini et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Related articles

No related content is available yet for this article.
 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

No related content is available yet for this article.

Article of the Year Award: Outstanding research contributions of 2021, as selected by our Chief Editors. Read the winning articles.