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CCR Focus

Aurora Kinases as Anticancer Drug Targets

Oliver Gautschi, Jim Heighway, Philip C. Mack, Phillip R. Purnell, Primo N. Lara Jr. and David R. Gandara
Oliver Gautschi
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Jim Heighway
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Philip C. Mack
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Phillip R. Purnell
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Primo N. Lara Jr.
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David R. Gandara
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DOI: 10.1158/1078-0432.CCR-07-2179 Published March 2008
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Abstract

The human aurora family of serine-threonine kinases comprises three members, which act in concert with many other proteins to control chromosome assembly and segregation during mitosis. Aurora dysfunction can cause aneuploidy, mitotic arrest, and cell death. Aurora kinases are strongly expressed in a broad range of cancer types. Aurora A expression in tumors is often associated with gene amplification, genetic instability, poor histologic differentiation, and poor prognosis. Aurora B is frequently expressed at high levels in a variety of tumors, often coincidently with aurora A, and expression level has also been associated with increased genetic instability and clinical outcome. Further, aurora kinase gene polymorphisms are associated with increased risk or early onset of cancer. The expression of aurora C in cancer is less well studied. In recent years, several small-molecule aurora kinase inhibitors have been developed that exhibit preclinical activity against a wide range of solid tumors. Preliminary clinical data from phase I trials have largely been consistent with cytostatic effects, with disease stabilization as the best response achieved in solid tumors. Objective responses have been noted in leukemia patients, although this might conceivably be due to inhibition of the Abl kinase. Current challenges include the optimization of drug administration, the identification of potential biomarkers of tumor sensitivity, and combination studies with cytotoxic drugs. Here, we summarize the most recent preclinical and clinical data and discuss new directions in the development of aurora kinase inhibitors as antineoplastic agents.

A defining characteristic of the malignant tumor cell is inappropriate growth. This aberrant behavior is accompanied by invasion into surrounding tissues and metastases to distant sites. The tumor cell phenotype is the consequence of a relatively high level of genetic instability, with sequential mutational and epimutational damage conferring growth and/or survival advantages to the tumor-initiating cell and its evolving progeny.

The mechanism of action of established and novel [reviewed in this issue (1–4)] cytotoxic chemotherapeutic agents essentially rests on the exploitation of tumor cell cycling to facilitate the preferential killing of tumor over normal host cells that are critical to survival. This selective killing may be achieved either by interfering with the synthesis/replication of DNA (e.g., using agents such as fluoropyrimidines, gemcitabine, or topoisomerase inhibitors), by the introduction of irresolvable lesions into the DNA of proliferating cells (e.g., platinum analogues and cyclophosphamide), or by disruption of the microtubule cytoskeleton essential for mitotic division (e.g., taxanes, Vinca alkaloids, and epothilones). Given that certain populations of normal and important cells also proliferate in adult tissues (e.g., in the bone marrow), it is not surprising that such cytotoxic agents are associated with some degree of severe normal tissue toxicity. Recent tumor genomics data, however, are now assisting in the development of more rationally selected drugs that target proteins expressed exclusively or at particularly high levels in tumor compared with essential normal adult cells. It is hoped that the specific pharmaceutical targeting of such proteins will result in a new generation of highly active drugs that are associated with minimal collateral host toxicity. We should also recognize, however, that given the underlying nature of the disease and the technology applied, many of the gene products so identified in analyses of expression in tumor versus normal tissue are likely to be intimately associated with the proliferative state and, further, that pharmacologic agents targeting such molecules may therefore again essentially represent a general targeting of proliferating cells. Tumor selectivity would in this case most likely rest on any indirect differential effects of removing target function in the tumor versus critical normal host cells (5). Indeed, proteins intimately involved in the regulation of the cell cycle (6), particularly cell cycle–associated kinases (7, 8), have been suggested as possible new anticancer targets.

Although the topic for this issue of CCR Focus is new cytotoxic compounds, the distinction between cytotoxic and cytostatic, and even between chemotherapy and targeted therapy, is perhaps of less importance and with perhaps less underlying biological rationale in 2008 than it was previously. In fact, targeted agents, such as epidermal growth factor receptor inhibitor or antiangiogenic tyrosine kinase inhibitors, do shrink tumors in some patients (i.e., a cytotoxic effect), whereas emerging data suggest that exploitation of the molecular targets of standard chemotherapy (e.g., using ERCC1 as a predictive biomarker for platinum compounds) is now an achievable goal in the clinic. In this review, we will consider the hypotheses that aberrant expression of two serine-threonine mitotic kinases, aurora A (encoded by AURKA on 20q13.2-13.31) and aurora B (encoded by AURKB on 17p13.1), contributes to the neoplastic phenotype; that aurora kinases are appropriate drug targets; and that inhibitors of these particular aurora kinases can add to the cancer therapeutic armamentarium, whether viewed as cytotoxic antineoplastics or as targeted agents capable of modulating the cytotoxicity of contemporary chemotherapy regimens.

Aurora Kinases

The aurora family comprises three related kinases that share the highest degree of sequence homology in their catalytic domains (9, 10). Expression of aurora A and B is closely linked to the proliferation of many, if not all, cell types, whereas for aurora C, the normal function of which is not clear, expression seems to be restricted to normal testicular tissue (11). Experimental data suggest that inappropriately high or low levels of aurora kinase activity are linked to genetic instability (12). Despite their sequence homology and common association with cycling cells, the subcellular distribution, partners, and substrates and therefore functions of aurora A and B are essentially nonoverlapping (Fig. 1; see refs. 8, 9, 12–14 for reviews).

Fig. 1.
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Fig. 1.

Cell cycle execution points and targets of aurora A and B kinases. Substrates phosphorylated in each phase of the cell cycle by each kinase are detailed, with orange circles denoting targets of aurora A and green circles denoting targets of aurora B. Orange/green line, known substrates of the single yeast aurora kinase IpI1p. Adapted with permission from Macmillan Publishers Ltd: Oncogene (13), 2005.

Aurora A has well-established but perhaps not yet fully understood roles in centrosome function and duplication, mitotic entry, and bipolar spindle assembly. By the G2 phase of the cell cycle through anaphase, it can be detected in the pericentriolar material. Additionally, it spreads to mitotic spindle poles and midzone microtubules during metaphase (9). Following activation by the LIM protein ajuba in G2, aurora A phosphorylates and recruits several microtubule-associated proteins to the centrosome to promote maturation. After the breakdown of the nuclear envelope, inactive cytoplasmic aurora A is transported to the proximal ends of the microtubules and activated by the spindle protein TPX2, where it plays an as yet not fully defined role in the Ran-spindle assembly process (9, 13). Aurora A is also linked to the process of G2-M transition, with suppression of expression leading to G2-M arrest and apoptosis and ectopic expression leading to bypass of the G2-M DNA damage-activated checkpoint in model systems (15, 16). In experimental murine models, overexpression of aurora A was found to be oncogenic (17, 18).

Aurora B is the catalytic component of the chromosomal passenger complex, which is composed of three additional noncatalytic subunits that direct its activity: survivin, INCEP, and borealin. The chromosomal passenger complex orchestrates the accurate segregation of the chromatids at mitosis, histone modification, and cytokinesis (19). Aurora B and its chromosomal passenger complex partners are associated with the centromeres from prometaphase to metaphase. After chromatid separation, they relocate to the midzone and remain at the midbody until the completion of cytokinesis (9). Aurora B function has been linked to chromatin modification in relation to the phosphorylation of histone H3 at Ser10 and Ser28 (20), events that may be required for chromosome condensation. Through the phosphorylation of MCAK, this kinase also has a crucial role in the regulation of accurate chromatid separation, with aurora B activity ensuring that mitosis does not proceed until all chromosomes have bipolar undertension attachments (21). Aurora B is also thought to be involved in the recruitment of spindle checkpoint proteins to the kinetochores. Finally, this kinase has a critical role in cytokinesis, with depletion resulting in polyploidy cells as a consequence of cytokinesis failure (9). High-level expression of aurora B in model systems has been linked to chromosome instability (22, 23).

Aurora C does not seem to have a role in mitosis in the majority of normal cells, with expression essentially restricted to the testes. Localizing in a similar pattern to aurora B, it is thought that aurora C is also a catalytic chromosomal passenger protein. Indeed, it has been shown that aurora C can rescue aurora B–depleted cells, suggesting some significant overlap in function (24). It is therefore thought likely that aurora C has a specific role in the regulation of chromosome segregation during male meiosis (25).

Aurora Kinases as Anticancer Targets: Preclinical Data

In a wide range of tumor types compared with essentially nonproliferating matched normal tissue, aurora A is strongly expressed at high frequency. This high level of expression is often associated with amplification of the region of chromosome 20 encoding AURKA (Table 1), indicating that deregulated expression of at least one gene in the amplified region provides a survival/proliferation advantage to the tumor cell and is therefore linked directly to neoplasia. In contrast, the chromosomal region encompassing AURKB does not seem to be amplified to a high level in tumors, although low-level copy number increases have been noted in non–small cell lung cancer (NSCLC; ref. 26). The AURKB gene, however, has also been shown to be strongly expressed in many tumor types compared with essentially nonproliferating matched normal tissue, with expression levels often correlating with disease characteristics or outcome (Figs. 2 and 3; Table 1). For example, we determined the expression of both aurora A and aurora B by immunohistochemistry in 33 patients with previously untreated, advanced NSCLC (Fig. 2).4 Our study revealed strong nuclear staining for aurora A (Fig. 2A) and aurora B (Fig. 2B) in 12 (36%) and 7 (21%) cases, respectively. Furthermore, aurora A positivity correlated with aurora B positivity (P = 0.01, Fisher's exact test) and with p53 overexpression (P = 0.05). When considering such data, it should be noted that the differential expression of a gene in tumor compared with normal tissue per se may be a poor indicator of causal involvement in neoplasia, given that this expression may simply be appropriate for the current physiologic state of the tumor cells. This may be particularly relevant in the context of cell cycle–associated genes such as aurora kinases, which are dramatically up-regulated in highly proliferating compared with nonproliferating cells. Thus, elevated AURKA or AURKB tumor expression may be an indicator of rapid cell division, an effect rather than a cause of the malignant phenotype. Such a possibility is supported by the concurrent up-regulation of both AURKA and AURKB transcription observed in tumors (26). In addition, to show that AURKB is strongly expressed in the majority of NSCLC cases with high-level expression of the gene correlating with poor survival and tumor genetic instability, however, we have also shown that, in most informative cases, this expression seems to be driven from one chromosomal allele (26). These observations are consistent with the hypothesis that up-regulation of the gene occurs through somatically acquired cis-located genetic damage, implicating aberrant deregulated expression of AURKB in NSCLC carcinogenesis. Aurora C expression has also been noted in some tumor cell lines, but the significance of this observation is not yet clear (11).

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Table 1.

Aurora kinases in cancer

Fig. 2.
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Fig. 2.

Coexpression of aurora A and aurora B in lung cancer. Representative aurora immunohistochemistry in NSCLC, showing coexpression of aurora A (A) and aurora B (B). Bar, 50 μm. (O. Gautschi et al., unpublished data).

Fig. 3.
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Fig. 3.

Prognostic significance of aurora B expression in lung cancer. Aurora B mRNA levels in 39 patients with NSCLC were quantified by real-time reverse transcription-PCR. Patients with excessive (above median) expression had a significantly (P = 0.028, Kaplan-Meier curve, log-rank test) poorer survival than patients with moderate (below median) expression. Adapted with permission from Macmillan Publishers Ltd: British Journal of Cancer (26), 2005.

It would seem that activating mutations of aurora kinase genes are rare in human tumors (27). Several studies, however, have suggested that commonly occurring gene polymorphisms of AURKA and AURKB are associated with cancer risk or clinical outcome among diverse ethnic groups (Table 1). Although these data imply that differences in functionality or basal expression levels of these kinases may modify risk, perhaps through marginally increasing the level of genetic instability in normal cells (12), they do not provide additional supportive evidence for aurora kinases as potentially effective anticancer drug targets. In some ways, such a statement may seem to be counterintuitive. Yet, when considering such data, we must discriminate between the process of carcinogenesis and the therapeutic utility of targeting a particular protein in an established tumor. For example, if a particular base change alters gene function in such a way as to marginally increase the chance of genetic instability in a particular cell type, this genotype may strongly modify the lifetime risk of tumorigenesis for a carrier. Despite being strongly implicated in elevated cancer risk, however, the gene product may still not be an effective anticancer drug target in relation to the clinical treatment of recognizable disease. Simply, once the horse has gone, fixing the lock on the stable door will not bring it back.

The clearly established involvement of aurora kinases in the process of mitosis and the strong circumstantial evidence suggesting that deregulated expression of aurora A and B is linked to tumorigenesis spurred the drive to identify pharmacologically active small-molecule inhibitors of these kinases. The compounds identified reacted with more than one kinase subtype or else were specific for one or other aurora kinase (Table 2). In vivo studies with several of these agents were promising, showing that they were able to bring about a profound inhibition of tumor growth in a range of model systems (28–30). Coupled with the genomic data, such studies provided a strong rationale to underpin subsequent clinical investigations. As is generally the case, however, it was not clear from the preclinical data whether aurora kinase inhibitors, if clinically active in humans, would function primarily as cytotoxic (associated with tumor cell death and response) or cytostatic (associated with growth inhibition and disease stabilization) agents. Ultimately, this question could only be addressed in clinical studies.

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Table 2.

Aurora kinase inhibitors in clinical development

Inhibitors of Aurora Kinases

Of the many aurora-selective small-molecule inhibitors currently undergoing preclinical and clinical assessment, only the clinically most advanced inhibitors are briefly discussed here, whereas many other promising members of this new drug class are in development (Table 2).

MK-0457 (VX-680) is a pyrimidine derivative with affinity for aurora A, B, and C at nanomolar concentrations. MK-0457 prevents cytokinesis but allows cells to progress through the other stages of mitosis, which leads to polyploidy and, in some cancer cell lines, massive apoptosis. In preclinical models, MK-0457 blocked tumor xenograft growth and induced tumor regressions (28). In its first phase I clinical trial, MK-0457 was given as an i.v. continuous infusion over several days to patients with previously treated solid tumors (31). The principal dose-limiting toxicity (DLT) was grade 3 neutropenia, accompanied by some nonspecific side effects, including low-grade nausea and fatigue. Disease stabilization was observed in one patient with lung cancer and in one patient with pancreatic cancer. Single-agent efficacy studies in lung cancer and colorectal cancer are ongoing.

AZD1152 is a quinazoline prodrug, which is converted in plasma into its active metabolite AZD1152-HQPA, which in turn has high affinity for aurora B and C. The effects of AZD1152-HQPA in cancer cells are comparable with MK-0457 (30). In preclinical models, AZD1152 significantly inhibited the growth of human tumor xenografts. In a phase I clinical trial, AZD1152 was given as a weekly 2-h infusion to patients with advanced, pretreated solid tumors (32). DLT was grade 3 neutropenia, with few nonhematologic toxicities. Pharmacokinetic studies confirmed rapid conversion of AZD1152 into AZD1152-HQPA. Three patients had stable disease (melanoma, nasopharyngeal carcinoma, and adenoid cystic carcinoma). Follow-up studies are ongoing with biweekly and continuous infusions, based on preclinical tumor models, which suggested that prolonged drug administration significantly increased the proapoptotic effect of AZD1152-HQPA.

PHA-739358 is a pan-aurora (A, B, and C) inhibitor with documented antitumor activity in multiple tumor xenograft models, which have shown sustained tumor growth inhibition after discontinuation of treatment. The results of two phase I dose-escalation studies are available (33). The first study tested 6-h i.v. infusions on days 1, 8, and 15 on a 4-week cycle in patients with advanced, pretreated solid tumors. In a preliminary assessment, DLT was reported to be grade 3 to 4 neutropenia. No tumor responses were observed, but 8 of 40 patients had stable disease for at least 4 months. Pretreatment and posttreatment skin biopsies showed down-regulation of phosphorylated histone H3 Ser10 levels in eight of nine patients tested. The second study tested 24-h infusions in a 2-week cycle. Again, DLT was reported to be grade 3 to 4 neutropenia. Nonhematologic toxicities, including fatigue, pyrexia, and diarrhea, were mild. Although no objective tumor responses were observed, 11 of 40 patients achieved disease stabilization. Posttreatment skin biopsies showed decreased phosphorylated histone H3 Ser10 levels in four of five patients tested. The recommended phase II dose was 500 mg/m2 without granulocyte colony-stimulating factor, whereas further dose escalation with filgastrim support is currently being investigated.

MLN8054 was the first orally available aurora kinase inhibitor and the first aurora A–selective inhibitor to enter human clinical trials. This compound induced mitotic accumulation and spindle defects and inhibited proliferation in multiple human cancer cell lines (34). Growth of human tumor xenografts in nude mice was inhibited after oral administration at well-tolerated doses, and the tumor growth inhibition was sustained after discontinuation of treatment. In xenografts, MLN8054 induced mitotic accumulation and apoptosis. The preliminary results of a phase I dose-escalation study are interesting for several reasons (35). Oral MLN8054 (daily on 7 consecutive days, 21-day intervals) was rapidly absorbed and displayed dose-proportionate exposure. DLT was found to be reversible grade 3 somnolence and no profound myelosuppression occurred. This was consistent with animal studies, which showed that MLN8054 binds to the γ-aminobutyric acid α 1 benzodiazepine receptor and causes reversible somnolence. Three human patients with metastatic colorectal cancer received eight cycles of treatment consistent with stable disease. Importantly, immunohistochemical analysis of skin biopsies did not show significant accumulation of cells in mitosis, suggesting incomplete target inhibition. Based on these results, the study is now escalating twice-daily dosing of MLN8054 over 14 days, with the coadministration of methylphenidate.

New Directions

Whether aurora A or aurora B is the better anticancer drug target is a matter of debate (8). At least two groups have directly addressed this question in the laboratory. Warner et al. (36) compared the effects of aurora A and aurora B antisense oligonucleotides in pancreatic cancer cells and found that aurora A–targeted therapy may be preferable to aurora B targeting, as shown by mitotic arrest and the rapid induction of apoptosis. Girdler et al. (37) compared the effects of RNA interference and small molecules targeting aurora A versus aurora B in colon cancer cells and found that the cells tested were extremely sensitive to aurora B inhibition. Interestingly, dual inhibition of aurora A and B results in phenotypes identical to inactivation of aurora B alone (28). Using RNA interference experiments, Yang et al. (38) showed that inactivation of aurora B indeed bypasses the requirement for aurora A and leads to polyploidy, indicating that aurora B is responsible for mitotic arrest in the absence of aurora A.

With the emergence of a large number of aurora kinase inhibitors, it will be interesting to see which, if any, of the currently available agents will have the requisite degree of antitumor activity in patients or merit further clinical development. Harrington et al. (28) showed that MK-0457 targets the FLT3 kinase and thereby ablated colony formation in primary acute myelogenous leukemia cells with FLT3 internal tandem duplications. Giles et al. (39) recently reported on the induction of clinical remission with MK-0457 in three patients with BCR-ABL–positive, pretreated leukemia and showed that MK-0457 blocked the T315I-mutant BCR-ABL kinase in these patients. These cases document the first objective responses to a kinase inhibitor in the T315I-mutant BCR-ABL and spurred ongoing clinical trials with MK-0457 in leukemia. The results also indicate that, analogous to sorafenib (which was initially designated as a RAF inhibitor and then later was found to additionally block angiogenesis), off-target effects may add to the successful clinical development of aurora kinase inhibitors. Further, we propose that the lack of objective tumor regression in early clinical trials of aurora kinase inhibitors in solid tumors warrants alternative assessments of antitumor activity in the phase II setting, such as the use of disease control rate (response rate plus stable disease), time-related end points, or randomized discontinuation study designs. This is especially relevant in the context of recent observations that some targeted agents (e.g., sorafenib and erlotinib) induced modest tumor regressions in phase II trials but have subsequently shown to improve survival outcomes in randomized phase III trials (40, 41).

Are the aurora kinase inhibitors cancer specific? Clearly, given that they are key regulators of mitosis, they are not, in the strictest sense. Indeed, neutropenia was the primary dose-limiting phase I toxicity in several studies, suggesting that these agents have collateral antiproliferation toxicity on the bone marrow. Aurora kinase inhibitors have also been shown to induce polyploidy in normal mammary epithelial cell cultures (42), raising the issue of long-term clinical effects. Clinical tolerability has generally been good, however, and no severe mucositis, peripheral neuropathy, diarrhea, or alopecia has been observed. One question for the future will therefore be: are there tumors that are exceptionally sensitive to such compounds, enabling delivery of minimally toxic doses that have significant antitumor effects? The identification of biomarkers predictive of clinical benefit for a particular drug in a particular patient may therefore be critical in relation to the effective development of new anticancer agents. In the future, it is likely that many new classes of biological marker, including mutational, epimutational, gene expression, and functional assays, will affect clinical decisions relating to which drug to use, at which dose, and in which patient. The collection of material to facilitate such studies will become increasingly important, especially in the larger clinical trials. The importance of biomarkers in evaluating the question of whether a drug hits a cellular target has also become increasingly accepted in oncology. This is especially true for newer drugs that may be associated with minimal toxicity and where the maximum tolerated dose may not be reached in phase I studies. One particularly attractive feature of the development of aurora kinase inhibitors is the availability of functional biomarkers of target effect. Analysis of phosphorylated histone H3 Ser10 levels can show the effects of both aurora A and aurora B inhibitors (Fig. 4). Because aurora A inhibition results in accumulation in mitosis, levels of phosphorylated histone H3 Ser10 may increase. In contrast, aurora B inhibition is expected to decrease the levels of phosphorylated histone H3 Ser10 because this is a direct substrate of aurora B kinase. As indicated by the translational study for PHA-739358 mentioned previously, confirmation of this as a sensitive and specific biomarker in clinical samples could offer the potential to bring a predictive biomarker to the clinic (33). Additional biomarkers have also been proposed. For example, Gizatullin et al. (43) studied the effect of cell cycle control on the effect of MK-0457 in cell lines from lung, breast, and colon cancer and found that a defective p53-p21 pathway was associated with increased sensitivity. Galvin et al. (44) reported on the use of the aurora A-T288 autophosphorylation site as pharmacodynamic markers for MLN8054. Mitotic index measurements coupled with the aurora A-T288 autophosphorylation site was a direct marker of aurora A activity in tumor and skin biopsies. These studies represent significant advances in the development of clinical biomarkers for aurora kinase inhibitors. Thus, predictive markers, and markers that allow determination of whether a drug is able to reach the target in a given patient, offer a great chance to achieve the truly individualized therapy that academic oncologists have imagined for the future.

Fig. 4.
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Fig. 4.

Induction of characteristic phenotypes by different aurora kinase inhibitors. A, in the A549 NSCLC cell line, aurora A–specific inhibitor MLN8054 induces monopolar spindles (inlay, green color), circular chromatin (inlay, purple color), and accumulation in mitosis (increased 4N peak in flow cytometry, increased phosphorylated histone H3 Ser10 staining). (O. Gautschi et al., unpublished data.) B, in contrast, aurora B/C–specific inhibitor ZM447439 in the A549 cell line allows for progression through mitosis, decreases phosphorylated histone H3 Ser10 staining, blocks cytokinesis, and induces polyploidy (appearance of 8N peak in flow cytometry). Reproduced from the Journal of Cell Biology, 2003;161:267-80. Copyright 2003 The Rockefeller University Press.

Several promising drug combinations, including aurora kinase inhibitors, are emerging. Setting the stage, Hata et al. (45) showed the synergistic enhancement of taxane activity in the presence of aurora A RNA interference in pancreatic cancer cells. Yang et al. (46) found that knockdown of aurora A by RNA interference reduced phosphorylated AKT levels and sensitized ovarian cancer cells to cisplatin. Sun et al. (47) described similar results in ovarian and lung cancer cells exposed to MK-0457 plus etoposide. Lee et al. (48) again described additive toxicity with MK-0457 and doxorubicin in prostate cancer cells, whereas Tanaka et al. (49) reported significantly enhanced docetaxel activity by aurora A short hairpin RNA in esophageal cancer xenografts in vivo. Tao et al. (50) showed preliminary data indicating that AZD1152 increased radiosensitivity in vivo and that this effect was p53 and cell cycle dependent. How aurora kinase targeting interacts with chemotherapy and radiation at the molecular and cell cycle level remains to be determined, but these results are very encouraging and will affect the design of clinical studies with aurora kinase inhibitors in the near future.

Conclusion

Genetic instability is a key driver of carcinogenesis, and there is ample evidence to suggest that deregulation of aurora kinases contributes to the acquisition of genetic aberrations, promoting the development of malignancy. The importance of aurora kinases as anticancer targets remains to be defined by ongoing clinical trials. Current trials are also aiming to define optimal drug schedules and to maximize target inhibition. At present, no predictive biomarker is available to select patients for treatment with an aurora kinase inhibitor, and further progress in this area is needed. Accumulating preclinical data point toward additive or even synergistic anticancer effects between aurora kinase inhibitors and conventional chemotherapy, and much hope lies on the translation of such combinations into the clinic.

Acknowledgments

We thank Millennium Pharmaceuticals (Cambridge, MA) for providing MLN8054, Dr. R. Gandour-Edwards (University of California Davis Medical Center, Sacramento, CA) for interpretation of the immunohistochemistry, and Dr. K. Chansky (Southwest Oncology Group Statistical Center, Seattle, WA) for statistical analysis.

Footnotes

  • Grant support: Swiss National Science Foundation (O. Gautschi), Swiss Cancer League (O. Gautschi), AstraZeneca Pharmaceuticals (O. Gautschi), and Millennium Pharmaceuticals (P.C. Mack and P.N. Lara, Jr.).

  • ↵4Unpublished data.

  • Received September 18, 2007.
  • Revision received January 10, 2008.
  • Accepted January 11, 2008.

References

  1. ↵
    1. Teicher BA
    . Newer cytotoxic agents: attacking cancer broadly. Clin Cancer Res 2008;14:1650–7.
    OpenUrl
    1. Choy H,
    2. Park C,
    3. Yao M
    . Current status and future prospect for satraplatin: an oral platinum analogue. Clin Cancer Res 2008;14:1618–23.
    OpenUrlAbstract/FREE Full Text
    1. Lee JJ,
    2. Swain SM
    . The epothilones: translating from the laboratory to the clinic. Clin Cancer Res 2008;14:1643–9.
    OpenUrl
  2. ↵
    1. Bennouna J,
    2. Delord JP,
    3. Campone M,
    4. Nguyen L
    . Vinflunine: a new microtubule inhibitor agent. Clin Cancer Res 2008:1610–17.
  3. ↵
    1. Sharma SV,
    2. Fischbach MA,
    3. Haber DA,
    4. Settleman J
    . “Oncogenic shock”: explaining oncogene addiction through differential signal attenuation. Clin Cancer Res 2006;12:4392–5s.
    OpenUrlCrossRef
  4. ↵
    1. Perez de Castro I,
    2. de Carcer G,
    3. Malumbres M
    . A census of mitotic cancer genes: new insights into tumor cell biology and cancer therapy. Carcinogenesis 2007;28:899–912.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Malumbres M,
    2. Barbacid M
    . Cell cycle kinases in cancer. Curr Opin Genet Dev 2007;17:60–5.
    OpenUrlCrossRefPubMed
  6. ↵
    1. Keen N,
    2. Taylor S
    . Aurora-kinase inhibitors as anticancer agents. Nat Rev Cancer 2004;4:927–36.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Fu J,
    2. Bian M,
    3. Jiang Q,
    4. Zhang C
    . Roles of aurora kinases in mitosis and tumorigenesis. Mol Cancer Res 2007;5:1–10.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Ducat D,
    2. Zheng Y
    . Aurora kinases in spindle assembly and chromosome segregation. Exp Cell Res 2004;301:60–7.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Kimura M,
    2. Matsuda Y,
    3. Yoshioka T,
    4. Okano Y
    . Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J Biol Chem 1999;274:7334–40.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Giet R,
    2. Petretti C,
    3. Prigent C
    . Aurora kinases, aneuploidy and cancer, a coincidence or a real link? Trends Cell Biol 2005;15:241–50.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Andrews PD
    . Aurora kinases: shining lights on the therapeutic horizon? Oncogene 2005;24:5005–15.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Marumoto T,
    2. Zhang D,
    3. Saya H
    . Aurora-A—a guardian of poles. Nat Rev Cancer 2005;5:42–50.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Cazales M,
    2. Schmitt E,
    3. Montembault E,
    4. Dozier C,
    5. Prigent C
    . CDC25B phosphorylation by aurora-A occurs at the G2/M transition and is inhibited by DNA damage. Cell Cycle 2005;4:1233–8.
    OpenUrlPubMed
  14. ↵
    1. Du J,
    2. Hannon GJ
    . Suppression of p160ROCK bypasses cell cycle arrest after aurora-A/STK15 depletion. Proc Natl Acad Sci U S A 2004;101:8975–80.
    OpenUrlAbstract/FREE Full Text
  15. ↵
    1. Bischoff JR,
    2. Anderson L,
    3. Zhu Y,
    4. et al
    . A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 1998;17:3052–65.
    OpenUrlAbstract
  16. ↵
    1. Zhou H,
    2. Kuang J,
    3. Zhong L,
    4. et al
    . Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 1998;20:189–93.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Vader G,
    2. Medema RH,
    3. Lens SM
    . The chromosomal passenger complex: guiding aurora-B through mitosis. J Cell Biol 2006;173:833–7.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Monier K,
    2. Mouradian S,
    3. Sullivan KF
    . DNA methylation promotes aurora-B-driven phosphorylation of histone H3 in chromosomal subdomains. J Cell Sci 2007;120:101–14.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Dewar H,
    2. Tanaka K,
    3. Nasmyth K,
    4. Tanaka TU
    . Tension between two kinetochores suffices for their bi-orientation on the mitotic spindle. Nature 2004;428:93–7.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Ota T,
    2. Suto S,
    3. Katayama H,
    4. et al
    . Increased mitotic phosphorylation of histone H3 attributable to AIM-1/aurora-B overexpression contributes to chromosome number instability. Cancer Res 2002;62:5168–77.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Hontz AE,
    2. Li SA,
    3. Lingle WL,
    4. et al
    . Aurora A and B overexpression and centrosome amplification in early estrogen-induced tumor foci in the Syrian hamster kidney: implications for chromosomal instability, aneuploidy, and neoplasia. Cancer Res 2007;67:2957–63.
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Sasai K,
    2. Katayama H,
    3. Stenoien DL,
    4. et al
    . Aurora-C kinase is a novel chromosomal passenger protein that can complement aurora-B kinase function in mitotic cells. Cell Motil Cytoskeleton 2004;59:249–63.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Tang CJ,
    2. Lin CY,
    3. Tang TK
    . Dynamic localization and functional implications of aurora-C kinase during male mouse meiosis. Dev Biol 2006;290:398–410.
    OpenUrlCrossRefPubMed
  24. ↵
    1. Smith SL,
    2. Bowers NL,
    3. Betticher DC,
    4. et al
    . Overexpression of aurora B kinase (AURKB) in primary non-small cell lung carcinoma is frequent, generally driven from one allele, and correlates with the level of genetic instability. Br J Cancer 2005;93:719–29.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Greenman C,
    2. Stephens P,
    3. Smith R,
    4. et al
    . Patterns of somatic mutation in human cancer genomes. Nature 2007;446:153–8.
    OpenUrlCrossRefPubMed
  26. ↵
    1. Harrington EA,
    2. Bebbington D,
    3. Moore J,
    4. et al
    . VX-680, a potent and selective small-molecule inhibitor of the aurora kinases, suppresses tumor growth in vivo. Nat Med 2004;10:262–7.
    OpenUrlCrossRefPubMed
    1. Soncini C,
    2. Carpinelli P,
    3. Gianellini L,
    4. et al
    . PHA-680632, a novel aurora kinase inhibitor with potent antitumoral activity. Clin Cancer Res 2006;12:4080–9.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Wilkinson RW,
    2. Odedra R,
    3. Heaton SP,
    4. et al
    . AZD1152, a selective inhibitor of aurora B kinase, inhibits human tumor xenograft growth by inducing apoptosis. Clin Cancer Res 2007;13:3682–8.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Rubin EH,
    2. Shapiro GI,
    3. Stein MN,
    4. et al
    . A phase I clinical and pharmacokinetic (PK) trial of the aurora kinase (AK) inhibitor MK-0457 in cancer patients [abstr 3009]. J Clin Oncol 2006;24 (June 20 Supplement).
  29. ↵
    1. Schellens JH,
    2. Boss D,
    3. Witteveen PO
    . Phase I and pharmacological study of the novel aurora kinase inhibitor AZD1152. J Clin Oncol 2006;24:122s.
    OpenUrl
  30. ↵
    1. De Jonge M
    . A phase I dose-escalation study of PHA-739358 administered as a 6-hour infusion on days 1, 8, and 15 every 4 weeks in patients with advanced/metastatic solid tumors. Presented at the VIII Congress of the Italian Association of Medical Oncology (AIOM), November 18, 2006, Milan, Italy.
  31. ↵
    1. Manfredi MG,
    2. Ecsedy JA,
    3. Meetze KA,
    4. et al
    . Antitumor activity of MLN8054, an orally active small-molecule inhibitor of aurora A kinase. Proc Natl Acad Sci U S A 2007;104:4106–11.
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Jones SF,
    2. Cohen RB,
    3. Dees EC,
    4. et al
    . Phase I clinical trial of MLN8054, a selective inhibitor of aurora A kinase. Proc Am Soc Clin Oncol Annu Meet 2007;25:3577.
    OpenUrl
  33. ↵
    1. Warner SL,
    2. Munoz RM,
    3. Stafford P,
    4. et al
    . Comparing aurora A and aurora B as molecular targets for growth inhibition of pancreatic cancer cells. Mol Cancer Ther 2006;5:2450–8.
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Girdler F,
    2. Gascoigne KE,
    3. Eyers PA,
    4. et al
    . Validating aurora B as an anti-cancer drug target. J Cell Sci 2006;119:3664–75.
    OpenUrlAbstract/FREE Full Text
  35. ↵
    1. Yang H,
    2. Burke T,
    3. Dempsey J,
    4. et al
    . Mitotic requirement for aurora A kinase is bypassed in the absence of aurora B kinase. FEBS Lett 2005;579:3385–91.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Giles FJ,
    2. Cortes J,
    3. Jones D,
    4. Bergstrom D,
    5. Kantarjian H
    . MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Blood 2007;109:500–2.
    OpenUrlAbstract/FREE Full Text
  37. ↵
    1. Shepherd FA,
    2. Rodrigues Pereira J,
    3. Ciuleanu T,
    4. et al
    . Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005;353:123–32.
    OpenUrlCrossRefPubMed
  38. ↵
    1. Escudier B,
    2. Eisen T,
    3. Stadler WM,
    4. et al
    . Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125–34.
    OpenUrlCrossRefPubMed
  39. ↵
    1. Ditchfield C,
    2. Johnson VL,
    3. Tighe A,
    4. et al
    . Aurora B couples chromosome alignment with anaphase by targeting BubR1, Mad2, and Cenp-E to kinetochores. J Cell Biol 2003;161:267–80.
    OpenUrlAbstract/FREE Full Text
  40. ↵
    1. Gizatullin F,
    2. Yao Y,
    3. Kung V,
    4. Harding MW,
    5. Loda M
    . The aurora kinase inhibitor VX-680 induces endoreduplication and apoptosis preferentially in cells with compromised p53-dependent postmitotic checkpoint function. Cancer Res 2006;66:7668–77.
    OpenUrlAbstract/FREE Full Text
  41. ↵
    1. Galvin KM,
    2. Huck J,
    3. Burenkova O,
    4. et al
    . Preclinical pharmacodynamic studies of aurora A inhibition by MLN8054. Proc Am Soc Clin Oncol Annu Meet 2007;24:13059.
    OpenUrl
  42. ↵
    1. Hata T,
    2. Furukawa T,
    3. Sunamura M,
    4. et al
    . RNA interference targeting aurora kinase A suppresses tumor growth and enhances the taxane chemosensitivity in human pancreatic cancer cells. Cancer Res 2005;65:2899–905.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Yang H,
    2. He L,
    3. Kruk P,
    4. Nicosia SV,
    5. Cheng JQ
    . Aurora-A induces cell survival and chemoresistance by activation of Akt through a p53-dependent manner in ovarian cancer cells. Int J Cancer 2006;119:2304–12.
    OpenUrlCrossRefPubMed
  44. ↵
    1. Sun C,
    2. Chan F,
    3. Briassouli P,
    4. Linardopoulos S
    . Aurora kinase inhibition downregulates NF-κB and sensitises tumour cells to chemotherapeutic agents. Biochem Biophys Res Commun 2007;352:220–5.
    OpenUrlCrossRefPubMed
  45. ↵
    1. Lee EC,
    2. Frolov A,
    3. Li R,
    4. Ayala G,
    5. Greenberg NM
    . Targeting aurora kinases for the treatment of prostate cancer. Cancer Res 2006;66:4996–5002.
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Tanaka E,
    2. Hashimoto Y,
    3. Ito T,
    4. et al
    . The suppression of aurora-A/STK15/BTAK expression enhances chemosensitivity to docetaxel in human esophageal squamous cell carcinoma. Clin Cancer Res 2007;13:1331–40.
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Tao Y,
    2. Zhang P,
    3. Girdler F,
    4. et al
    . Enhancement of radiation response in p53-deficient cancer cells by the Aurora-B kinase inhibitor AZD1152. Oncogene. 2007 Dec 17 [Epub ahead of print].
  48. ↵
    1. Tanaka T,
    2. Kimura M,
    3. Matsunaga K,
    4. Fukada D,
    5. Mori H
    . Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res 1999;59:2041–4.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Miyoshi Y,
    2. Iwao K,
    3. Egawa C,
    4. Noguchi S
    . Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers. Int J Cancer 2001;92:370–3.
    OpenUrlCrossRefPubMed
  50. ↵
    1. Hoque A,
    2. Carter J,
    3. Xia W,
    4. et al
    . Loss of aurora A/STK15/BTAK overexpression correlates with transition of in situ to invasive ductal carcinoma of the breast. Cancer Epidemiol Biomarkers Prev 2003;12:1518–22.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    1. Royce ME,
    2. Xia W,
    3. Sahin AA,
    4. et al
    . STK15/aurora-A expression in primary breast tumors is correlated with nuclear grade but not with prognosis. Cancer 2004;100:12–9.
    OpenUrlCrossRefPubMed
  52. ↵
    1. Xu HT,
    2. Ma L,
    3. Qi FJ,
    4. et al
    . Expression of serine threonine kinase 15 is associated with poor differentiation in lung squamous cell carcinoma and adenocarcinoma. Pathol Int 2006;56:375–80.
    OpenUrlCrossRefPubMed
  53. ↵
    1. Vischioni B,
    2. Oudejans JJ,
    3. Vos W,
    4. Rodriguez JA,
    5. Giaccone G
    . Frequent overexpression of aurora B kinase, a novel drug target, in non-small cell lung carcinoma patients. Mol Cancer Ther 2006;5:2905–13.
    OpenUrlAbstract/FREE Full Text
  54. ↵
    1. Li D,
    2. Zhu J,
    3. Firozi PF,
    4. et al
    . Overexpression of oncogenic STK15/BTAK/aurora A kinase in human pancreatic cancer. Clin Cancer Res 2003;9:991–7.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    1. Chieffi P,
    2. Cozzolino L,
    3. Kisslinger A,
    4. et al
    . Aurora B expression directly correlates with prostate cancer malignancy and influence prostate cell proliferation. Prostate 2006;66:326–33.
    OpenUrlCrossRefPubMed
  56. ↵
    1. Comperat E,
    2. Camparo P,
    3. Haus R,
    4. et al
    . Aurora-A/STK-15 is a predictive factor for recurrent behaviour in non-invasive bladder carcinoma: a study of 128 cases of non-invasive neoplasms. Virchows Arch 2007;450:419–24.
    OpenUrlCrossRefPubMed
  57. ↵
    1. Fraizer GC,
    2. Diaz MF,
    3. Lee IL,
    4. Grossman HB,
    5. Sen S
    . Aurora-A/STK15/BTAK enhances chromosomal instability in bladder cancer cells. Int J Oncol 2004;25:1631–9.
    OpenUrlPubMed
  58. ↵
    1. Tong T,
    2. Zhong Y,
    3. Kong J,
    4. et al
    . Overexpression of aurora-A contributes to malignant development of human esophageal squamous cell carcinoma. Clin Cancer Res 2004;10:7304–10.
    OpenUrlAbstract/FREE Full Text
  59. ↵
    1. Yang SB,
    2. Zhou XB,
    3. Zhu HX,
    4. et al
    . Amplification and overexpression of aurora-A in esophageal squamous cell carcinoma. Oncol Rep 2007;17:1083–8.
    OpenUrlPubMed
  60. ↵
    1. Araki K,
    2. Nozaki K,
    3. Ueba T,
    4. Tatsuka M,
    5. Hashimoto N
    . High expression of aurora-B/aurora and Ipll-like midbody-associated protein (AIM-1) in astrocytomas. J Neurooncol 2004;67:53–64.
    OpenUrlCrossRefPubMed
  61. ↵
    1. Zeng WF,
    2. Navaratne K,
    3. Prayson RA,
    4. Weil RJ
    . Aurora B expression correlates with aggressive behaviour in glioblastoma multiforme. J Clin Pathol 2007;60:218–21.
    OpenUrlAbstract/FREE Full Text
  62. ↵
    1. Jeng YM,
    2. Peng SY,
    3. Lin CY,
    4. Hsu HC
    . Overexpression and amplification of aurora-A in hepatocellular carcinoma. Clin Cancer Res 2004;10:2065–71.
    OpenUrlAbstract/FREE Full Text
  63. ↵
    1. Zhao X,
    2. Li FC,
    3. Li YH,
    4. et al
    . [Mutation of p53 and overexpression of STK15 in laryngeal squamous-cell carcinoma]. Zhonghua Zhong Liu Za Zhi 2005;27:134–7.
    OpenUrlPubMed
  64. ↵
    1. Li FC,
    2. Li YH,
    3. Zhao X,
    4. et al
    . [Deletion of p15 and p16 genes and overexpression of STK15 gene in human laryngeal squamous cell carcinoma]. Zhonghua Yi Xue Za Zhi 2003;83:316–9.
    OpenUrlPubMed
  65. ↵
    1. Reiter R,
    2. Gais P,
    3. Jutting U,
    4. et al
    . Aurora kinase A messenger RNA overexpression is correlated with tumor progression and shortened survival in head and neck squamous cell carcinoma. Clin Cancer Res 2006;12:5136–41.
    OpenUrlAbstract/FREE Full Text
  66. ↵
    1. Qi G,
    2. Ogawa I,
    3. Kudo Y,
    4. et al
    . Aurora-B expression and its correlation with cell proliferation and metastasis in oral cancer. Virchows Arch 2007;450:297–302.
    OpenUrlCrossRefPubMed
  67. ↵
    1. Sorrentino R,
    2. Libertini S,
    3. Pallante PL,
    4. et al
    . Aurora B overexpression associates with the thyroid carcinoma undifferentiated phenotype and is required for thyroid carcinoma cell proliferation. J Clin Endocrinol Metab 2005;90:928–35.
    OpenUrlCrossRefPubMed
  68. ↵
    1. Lassmann S,
    2. Shen Y,
    3. Jutting U,
    4. et al
    . Predictive value of aurora-A/STK15 expression for late stage epithelial ovarian cancer patients treated by adjuvant chemotherapy. Clin Cancer Res 2007;13:4083–91.
    OpenUrlAbstract/FREE Full Text
  69. ↵
    1. Landen CN,
    2. Jr.,
    3. Lin YG,
    4. Immaneni A,
    5. et al
    . Overexpression of the centrosomal protein aurora-A kinase is associated with poor prognosis in epithelial ovarian cancer patients. Clin Cancer Res 2007;13:4098–104.
    OpenUrlAbstract/FREE Full Text
  70. ↵
    1. Kurahashi T,
    2. Miyake H,
    3. Hara I,
    4. Fujisawa M
    . Significance of aurora-A expression in renal cell carcinoma. Urol Oncol 2007;25:128–33.
    OpenUrlPubMed
  71. ↵
    1. Bodvarsdottir SK,
    2. Hilmarsdottir H,
    3. Birgisdottir V,
    4. Steinarsdottir M,
    5. Jonasson JG
    . Aurora-A amplification associated with BRCA2 mutation in breast tumours. Cancer Lett 2007;248:96–102.
    OpenUrlCrossRefPubMed
  72. ↵
    1. Sen S,
    2. Zhou H,
    3. White RA
    . A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. Oncogene 1997;14:2195–200.
    OpenUrlCrossRefPubMed
  73. ↵
    1. Nishida N,
    2. Nagasaka T,
    3. Kashiwagi K,
    4. Boland CR,
    5. Goel A
    . High copy amplification of the Aurora-A gene is associated with chromosomal instability phenotype in human colorectal cancers. Cancer Biol Ther 2007;6:525–33.
    OpenUrlPubMed
  74. ↵
    1. Reichardt W,
    2. Jung V,
    3. Brunner C,
    4. et al
    . The putative serine/threonine kinase gene STK15 on chromosome 20q13.2 is amplified in human gliomas. Oncol Rep 2003;10:1275–9.
    OpenUrlPubMed
  75. ↵
    1. Klein A,
    2. Reichardt W,
    3. Jung V,
    4. Zang KD,
    5. Meese E
    . Overexpression and amplification of STK15 in human gliomas. Int J Oncol 2004;25:1789–94.
    OpenUrlPubMed
  76. ↵
    1. Neben K,
    2. Korshunov A,
    3. Benner A,
    4. et al
    . Microarray-based screening for molecular markers in medulloblastoma revealed STK15 as independent predictor for survival. Cancer Res 2004;64:3103–11.
    OpenUrlAbstract/FREE Full Text
  77. ↵
    1. Sen S,
    2. Zhou H,
    3. Zhang RD,
    4. et al
    . Amplification/overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst 2002;94:1320–9.
    OpenUrlAbstract/FREE Full Text
  78. ↵
    1. Tatsuka M,
    2. Sato S,
    3. Kitajima S,
    4. et al
    . Overexpression of aurora-A potentiates HRAS-mediated oncogenic transformation and is implicated in oral carcinogenesis. Oncogene 2005;24:1122–7.
    OpenUrlCrossRefPubMed
  79. ↵
    1. Moreno-Bueno G,
    2. Sanchez-Estevez C,
    3. Cassia R,
    4. et al
    . Differential gene expression profile in endometrioid and nonendometrioid endometrial carcinoma: STK15 is frequently overexpressed and amplified in nonendometrioid carcinomas. Cancer Res 2003;63:5697–702.
    OpenUrlAbstract/FREE Full Text
  80. ↵
    1. Chen J,
    2. Sen S,
    3. Amos CI,
    4. et al
    . Association between aurora-A kinase polymorphisms and age of onset of hereditary nonpolyposis colorectal cancer in a Caucasian population. Mol Carcinog 2007;46:249–56.
    OpenUrlCrossRefPubMed
  81. ↵
    1. Hienonen T,
    2. Salovaara R,
    3. Mecklin JP,
    4. Jarvinen H,
    5. Karhu A
    . Preferential amplification of AURKA 91A (Ile31) in familial colorectal cancers. Int J Cancer 2006;118:505–8.
    OpenUrlCrossRefPubMed
  82. ↵
    1. Ewart-Toland A,
    2. Briassouli P,
    3. de Koning JP,
    4. et al
    . Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human. Nat Genet 2003;34:403–12.
    OpenUrlCrossRefPubMed
  83. ↵
    1. Lo YL,
    2. Yu JC,
    3. Chen ST,
    4. et al
    . Breast cancer risk associated with genotypic polymorphism of the mitosis-regulating gene aurora-A/STK15/BTAK. Int J Cancer 2005;115:276–83.
    OpenUrlCrossRefPubMed
  84. ↵
    1. Vidarsdottir L,
    2. Bodvarsdottir SK,
    3. Hilmarsdottir H,
    4. Tryggvadottir L,
    5. Eyfjord JE
    . Breast cancer risk associated with AURKA 91T→A polymorphism in relation to BRCA mutations. Cancer Lett 2007;250:206–12.
    OpenUrlCrossRefPubMed
  85. ↵
    1. Cox DG,
    2. Hankinson SE,
    3. Hunter DJ
    . Polymorphisms of the AURKA (STK15/aurora kinase) gene and breast cancer risk (United States). Cancer Causes Control 2006;17:81–3.
    OpenUrlCrossRefPubMed
  86. ↵
    1. Tchatchou S,
    2. Wirtenberger M,
    3. Hemminki K,
    4. et al
    . Aurora kinases A and B and familial breast cancer risk. Cancer Lett 2007;247:266–72.
    OpenUrlCrossRefPubMed
  87. ↵
    1. Kimura MT,
    2. Mori T,
    3. Conroy J,
    4. et al
    . Two functional coding single nucleotide polymorphisms in STK15 (aurora-A) coordinately increase esophageal cancer risk. Cancer Res 2005;65:3548–54.
    OpenUrlAbstract/FREE Full Text
  88. ↵
    1. Gu J,
    2. Gong Y,
    3. Huang M,
    4. Lu C,
    5. Spitz MR
    . Polymorphisms of STK15 (aurora-A) gene and lung cancer risk in Caucasians. Carcinogenesis 2007;28:350–5.
    OpenUrlAbstract/FREE Full Text
  89. ↵
    1. Ju H,
    2. Cho H,
    3. Kim YS,
    4. et al
    . Functional polymorphism 57Val>Ile of aurora kinase A associated with increased risk of gastric cancer progression. Cancer Lett 2006;242:273–9.
    OpenUrlCrossRefPubMed
  90. ↵
    1. Ewart-Toland A,
    2. Dai Q,
    3. Gao YT,
    4. et al
    . Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene: a meta-analysis of multiple cancer types. Carcinogenesis 2005;26:1368–73.
    OpenUrlAbstract/FREE Full Text
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Clinical Cancer Research: 14 (6)
March 2008
Volume 14, Issue 6
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Aurora Kinases as Anticancer Drug Targets
Oliver Gautschi, Jim Heighway, Philip C. Mack, Phillip R. Purnell, Primo N. Lara Jr. and David R. Gandara
Clin Cancer Res March 15 2008 (14) (6) 1639-1648; DOI: 10.1158/1078-0432.CCR-07-2179

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Aurora Kinases as Anticancer Drug Targets
Oliver Gautschi, Jim Heighway, Philip C. Mack, Phillip R. Purnell, Primo N. Lara Jr. and David R. Gandara
Clin Cancer Res March 15 2008 (14) (6) 1639-1648; DOI: 10.1158/1078-0432.CCR-07-2179
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Clinical Cancer Research
eISSN: 1557-3265
ISSN: 1078-0432

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