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Aurora Kinase a in Gastrointestinal Cancers: Time to Target Ahmed Katsha1, Abbes Belkhiri1, Laura Goff3 and Wael El-Rifai1,2,4*

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Aurora Kinase a in Gastrointestinal Cancers: Time to Target Ahmed Katsha1, Abbes Belkhiri1, Laura Goff3 and Wael El-Rifai1,2,4* Katsha et al. Molecular Cancer (2015) 14:106 DOI 10.1186/s12943-015-0375-4 REVIEW Open Access Aurora kinase A in gastrointestinal cancers: time to target Ahmed Katsha1, Abbes Belkhiri1, Laura Goff3 and Wael El-Rifai1,2,4* Abstract Gastrointestinal (GI) cancers are a major cause of cancer-related deaths. During the last two decades, several studies have shown amplification and overexpression of Aurora kinase A (AURKA) in several GI malignancies. These studies demonstrated that AURKA not only plays a role in regulating cell cycle and mitosis, but also regulates a number of key oncogenic signaling pathways. Although AURKA inhibitors have moved to phase III clinical trials in lymphomas, there has been slower progress in GI cancers and solid tumors. Ongoing clinical trials testing AURKA inhibitors as a single agent or in combination with conventional chemotherapies are expected to provide important clinical information for targeting AURKA in GI cancers. It is, therefore, imperative to consider investigations of molecular determinants of response and resistance to this class of inhibitors. This will improve evaluation of the efficacy of these drugs and establish biomarker based strategies for enrollment into clinical trials, which hold the future direction for personalized cancer therapy. In this review, we will discuss the available data on AURKA in GI cancers. We will also summarize the major AURKA inhibitors that have been developed and tested in pre-clinical and clinical settings. Keywords: Aurora kinases, Therapy, AURKA inhibitors, MNL8237, Alisertib, Gastrointestinal, Cancer, Signaling pathways Introduction stage [9-11]. Furthermore, AURKA is critical for Mitotic kinases are the main proteins that coordinate ac- bipolar-spindle assembly where it interacts with Ran- curate mitotic processing [1]. In lower organisms, mitotic TPX2 pathway [12]. In addition to its role in mitosis, kinases include polo-like kinases, NIMA-related kinases, AURKA is recently reported to regulate stem cell self- cyclin-dependent kinase 1, WARTS/LATS1-related ki- renewal, reprogramming, and differentiation [13,14]. nases, and Aurora/Ipl1-related kinases [2]. In humans, Overexpression of AURKA has been reported to impair the aurora kinase family is considered homologous to DNA damage repair through inhibition recruitment of Aurora/Ipl1 kinases [2]. This family consists of highly RAD51 to double strands breaks [15]. Additionally, conserved serine-threonine kinases, which play a critical AURKA was found to suppress BRCA1 and BRCA2, role in regulation of mitotic events like spindle assem- both play a major role in DNA damage response bly, function of centrosomes and cytoskeleton, and cyto- [16,17]. Furthermore, AURKA was also reported to kinesis [3,4]. Members of this family are Aurora kinase regulate cell migration and adhesion [18] and to medi- A (AURKA), Aurora kinase B (AURKB), and Aurora ateanincreaseinVEGFmRNAexpression[19]. kinase C (AURKC) [3,4]. AURKA is located at chromo- AURKA activity is dependent on its phosphorylation at some 20q13.2 [5,6] and was found to play an important the 288-threonine residue (T288); located on the activa- role during mitosis. It has been shown that AURKA tion loop of the kinase. AURKA is activated through an knockdown suppresses centrosome maturation [7,8]. In autophosphorylation process upon binding with TPX2 mice, AURKA genetic ablation or null mutation leads to [12,20], along with several other kinases. AURKA mitotic arrest and embryonic death at the blastocyst signaling networks are summarized in Table 1 and Figure 1. * Correspondence: [email protected] Several studies have shown that AURKA is frequently 1 Department of Surgery, Vanderbilt University Medical Center, 760 PRB, 2220 amplified in several tumors including breast, leukemia, Pierce Avenue, 37232-6308 Nashville, TN, USA 2Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, USA Full list of author information is available at the end of the article © 2015 Katsha et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Katsha et al. Molecular Cancer (2015) 14:106 Page 2 of 13 Table 1 Selected cancer associated proteins regulated by AURKA Protein Type of regulation Functional significance References p53 Phospho-Ser215 Abrogates transactivation [48,56] Phospho-Ser315 Abrogates transactivation and enhances proteasomal degradation NF-κBp65 Phospho-Ser536 Promotes inflammation and cell survival [49] P73 Phospho-Ser235 Induces apoptosis [52-56] MDM2 Phospho-Ser166 Activates MDM2 and degradation of P53 [48] GSK3β Phospho-Ser9 Inhibits GSK3β and enhances β-catenin activity [19] IκBα Phospho-Ser32 Induces degradation of IκBα and activation of NF-κB pathway [49] JAK2 Increased expression Activates STAT3 [55] N-MYC Increased expression Stabilizes N-MYC protein [106] SRC Phospho-Tyr416 Activates SRC and promotes cancer cell invasion [18] IKKα/β Phospho-Ser176/180 Activates NF-κB pathway [107] NF-κB2/p100 Phospho-Ser866/870 Activates non-canonical NF-κB pathway [108] STAT3 Phospho-Tyr705 Promotes cell survival [55] RalA Phospho-Ser194 Enhances transformed cell growth [74] BRCA1/BRCA2 Decreased expression Down-regulate cell cycle and DNA damage response [16,17,109] bladder, ovarian, gastric, esophageal, liver, colorectal, and target in GI cancers. It will also summarize the recent pancreatic cancers [21-30]. Notably, AURKA overexpres- advancement of AURKA inhibitors in pre-clinical studies sion has been significantly associated with high-grade and clinical trials. (grade II-IV) and high-stage (stage IIIB-IV) hepatocellular carcinoma tumors [30]. Furthermore, it was suggested AURKA in gastrointestinal cancers that AURKA is an essential mediator of chemoresistance Cancers can develop in any anatomical site of the GI in colorectal and breast cancers [31,32]. Importantly, sev- system including esophagus, stomach, small intestine, eral studies indicated that AURKA overexpression dir- colon, rectum, liver, gall bladder, and pancreas. A cancer ectly leads to malignant transformation and tumor in any of these organs represents a unique type where formation [25,33,34]. Additionally, AURKA inhibition or different molecular mechanisms of tumorigenesis can knockdown was shown to induce senescence in multiple exist. Recent studies have shown that AURKA is fre- myeloma [35] and colon cancer cells [36]. Together, these quently overexpressed and/or amplified in several GI findings strongly suggest the key role of AURKA in cancers [25-28]. In the following sections, we will review tumorigenesis, and thus, underscore AURKA as an at- and discuss some of the recently reported studies about tractive target for cancer therapy. AURKA functions in GI cancers. Gastrointestinal (GI) Cancers are a leading cause of cancer-related deaths in the world. In fact, gastric cancer AURKA in upper gastrointestinal cancers is the second cause of cancer deaths [37], whereas Upper gastrointestinal (UGI) cancers include tumors of esophageal neoplasm is the eighth most common cancer the stomach and esophagus. While esophageal squamous worldwide and its incidence, especially adenocarcinoma cell carcinoma (ESCC) is the predominant histological type, is continuously increasing [38]. At the same time, type of esophageal cancers in the world, there has been colorectal cancer is the third most common cancer a significant increase in the incidence of gastroesopha- worldwide [39]. In 2013, more than 30,000 new cases of geal reflux-related esophageal adenocarcinomas (EAC) liver cancer were estimated in men and women in the in the Western world [41]. The majority of gastric cancers United States [40]. Similarly, more than 45,000 new are adenocarcinomas; other subtypes such as lymphomas cases of pancreatic cancer were estimated in the US in and gastrointestinal stromal tumors are rare and will not 2014 while its survival rate hardly improved in the last be discussed in this review. Amplifications of chromo- three to four decades [40]. The development of new somal region 20q13, where AURKA is located, have been treatment modalities and targeted therapy approaches, described in gastric and esophageal cancers [42,43]. Poly- based on the molecular features of the tumor, is urgently morphisms in the AURKA gene have also been reported needed to improve the dismal survival rates of these in UGI cancers [44,45]. Several studies have shown fre- highly prevalent cancers worldwide. This review will quent overexpression of AURKA at the mRNA and pro- focus on AURKA as a potential molecular therapeutic tein levels in ESCC, EAC, and gastric cancers [28,46-49]. Katsha et al. Molecular Cancer (2015) 14:106 Page 3 of 13 Figure 1 A summary of signaling networks of AURKA in cancer. Solid lines indicate direct regulation, whereas dashed lines indicate indirect regulation. It has also been suggested that the increased AURKA ex- Furthermore, it has been shown that AURKA can regulate pression might be used as a prognostic marker of ESCC and suppress GSK3β kinase activity in gastric cancer cell [50]. In addition, overexpression of AURKA in premalig- lines [19]. The AURKA-GSK3β
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