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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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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 Rancurate 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 selfcyclin-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 mediA (AURKA), Aurora kinase B (AURKB), and Aurora ate an increase in VEGF mRNA expression [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 activarole 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 amplified in several tumors including breast, leukemia,

1Department of Surgery, Vanderbilt University Medical Center, 760 PRB, 2220 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

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Table 1 Selected cancer associated proteins regulated by AURKA

  • Protein
  • Type of regulation

Phospho-Ser215 Phospho-Ser315 Phospho-Ser536 Phospho-Ser235 Phospho-Ser166 Phospho-Ser9

  • Functional significance
  • References

  • p53
  • Abrogates transactivation
  • [48,56]

Abrogates transactivation and enhances proteasomal degradation Promotes inflammation and cell survival Induces apoptosis
NF-κBp65 P73
[49] [52-56]

  • [48]
  • MDM2

GSK3β

IκBα

Activates MDM2 and degradation of P53 Inhibits GSK3β and enhances β-catenin activity Induces degradation of IκBα and activation of NF-κB pathway Activates STAT3
[19]

  • Phospho-Ser32
  • [49]

  • JAK2
  • Increased expression

Increased expression Phospho-Tyr416 Phospho-Ser176/180 Phospho-Ser866/870 Phospho-Tyr705 Phospho-Ser194 Decreased expression
[55]
N-MYC SRC

  • Stabilizes N-MYC protein
  • [106]

  • [18]
  • Activates SRC and promotes cancer cell invasion

  • Activates NF-κB pathway
  • IKKα/β

NF-κB2/p100 STAT3
[107] [108] [55]
Activates non-canonical NF-κB pathway Promotes cell survival

  • RalA
  • Enhances transformed cell growth

Down-regulate cell cycle and DNA damage response
[74]
BRCA1/BRCA2

[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 fremyeloma [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 gastroesophaworldwide [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 chromothree 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]. Polybased 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 frehighly prevalent cancers worldwide. This review will quent overexpression of AURKA at the mRNA and profocus 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

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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 interaction activates β- nant and malignant histological stages of reflux-induced catenin/TCF transcription complex, which leads to Barrett’s tumorigenesis has been reported [51]. Similarly, increased mRNA expression of several oncogenic prooverexpression of AURKA has been observed in early teins such as CCND1, c-MYC, c-MYC-binding protein, pre-neoplastic stages of gastric cancer in mouse models CLDN1, FGF18, and VEGF [19]. Pro-inflammatory signaland human [49]. Taken together, these reports strongly ing is a significant component in the etiology of tumor

  • suggest a critical role for AURKA in carcinogenesis.
  • development and progression of UGI cancers. In this

Molecular studies have shown that AURKA promotes context, recent reports indicated that AURKA overexcell survival signaling while it suppresses the pro- pression promotes activation of NF-κB [49] and STAT3 apoptotic machinery in UGI cancer cells [52,53]. We [55] pathways in these cancers. In these studies, and others have reported that AURKA promotes acti- AURKA inhibition abrogates the pro-survival and provation of the AKT pro-survival signaling pathway [47,54]. inflammatory signaling mediated by NF-κB and STAT3

Katsha et al. Molecular Cancer (2015) 14:106

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with suppression of key pro-survival target genes such leads to chromosomal instability. In normal cells, expresas BCL-xL, BCL2, and MCL1 [49,55]. Some of the main sion of AURKA protein is predominantly confined to the features of cancer cells include resistance to pro- nucleus and subject to spatio-temporal regulation during apoptotic stimuli and the ability to overcome genotoxic mitotic progression. In contrast, expression of AURKA stress and chemotherapeutic-induced death. We and others protein is frequently observed in the cytoplasm, in have shown that AURKA can suppress p53 pro-apoptotic addition to the nucleus, in cancer cells, suggesting an functions [48,56]. A recent study has shown that AURKA extended role of AURKA beyond regulation of mitosis regulates the key ubiquitin ligase involved in degradation [62]. This finding provides additional evidence supportof p53, HDM2, whereby overexpression of AURKA en- ing the wealth of signaling data for AURKA reported in hanced HDM2 stabilization and promoted degradation of upper GI cancers (summarized in the section above). For p53, thereby abrogating p53 pro-apoptotic function in re- instance, Tseng and colleagues found that AURKA ensponse to chemotherapy [48]. Not only does AURKA cir- hances formation and aggregation of mutant Ras cumvent p53 pathway, but it also provides a mechanism (RasV12) through regulation of RAS/MEK/ERK pathfor cancer cells to evade apoptosis by suppressing p73, an ways and AKT phosphorylation in colon cancer [63]. important p53 family protein [52,56]. Collectively, these Aurora kinase pharmacological inhibition sensitized signaling mechanisms mediated by AURKA can pro- colon cancer cells to Tumor necrosis factor (TNF) and mote cancer cell survival and provide a chemoresistance TNF-related apoptosis-inducing ligand (TRAIL) [64]. phenotype. These findings also suggest AURKA as part In addition, AURKA inhibition, using specific or pan of a signaling hub controlling several key pathways that Aurora kinase inhibitors, sensitized colon cancer cells

  • regulate the hallmarks of the cancer cell network.
  • to chemotherapy [65], TNF or TRAIL induced apop-

Several AURKA inhibitors have been developed to tosis [64] as well as mitotic failure and cell death when overcome AURKA-mediated pro-survival and anti- inhibited along with SRC [66]. Other reports showed apoptotic activities in cancer cells. Inhibition of AURKA that pharmacological inhibition of AURKA with using investigational MLN8054 or MLN8237 led to MLN8054 in colon cancer HCT-116 xenografts inreversal of anti-apoptotic signaling cascades with activa- duces senescence in vivo [36]. These findings suggest tion of pro-apoptotic p73 in p53 deficient cells with re- that more studies are needed to better characterize the expression of several pro-apoptotic proteins such as role of AURKA in colon cancer signaling and PUMA, NOXA, and p21 [52]. AURKA inhibition by small therapeutics. molecule MLN8237 as a single agent or in combination with Cisplatin or Docetaxel significantly enhanced cell death in esophageal adenocarcinoma xenograft mouse

AURKA in pancreatic cancer

model [53,57]. These findings strongly indicate that Overexpression of AURKA was reported in pancreatic AURKA could be an important therapeutic target in cancer [26], in the early stages of abnormalities in pan-

  • upper GI cancers.
  • creatic ducts and ductal dysplasia in transgenic mouse

model for pancreatic cancer [67], and linked to chromosome instability and centrosome abnormality [68]. As

AURKA in colorectal cancer

Colorectal cancer (CRC) was one of the first cancers observed in other GI cancers, suppression of AURKA found to have AURKA amplification. A 1998 study using RNA interference [69] or small molecule inhibitor showed that overexpression of AURKA resulted in SNS-314 [70] suppresses tumor growth and enhances centrosome amplification, chromosomal instability and chemosensitivity. Similar results were obtained with transformation in mammalian cells, including colon can- specific AURKA inhibitor CYC3 in combination with cer cells [34]. Genetic variations in the AURKA gene Paclitaxel [71]. In addition, AURKA plays a role in prowere also detected and associated with aneuploidy in hu- tecting human pancreatic ductal adenocarcinoma cells man colon tumors and low penetrance CRC susceptibil- from autophagic cell death induced by metabolic stress ity factor [58,59]. AURKA overexpression was associated [72]. Interestingly, while it was shown in colorectal canwith the down-regulation of checkpoint with forkhead cer that AURKA regulates MEK/ERK pathway [63], it and ring finger domains (CHFR) in colorectal cancers was reported that AURKA is a downstream target of with high microsatellite instability [60]. Importantly, re- this pathway in pancreatic cancer [73], raising the possicent reports indicated that AURKA is critical for tumori- bility of an existing positive feedback loop between genicity and chemoresistance in CRC stem cells [31], AURKA and MEK/ERK pathway. This signaling loop and suggested AURKA as a predictive marker for recur- further underscores the potential therapeutic benefit of rence in stage III in colon tumors lacking microsatellite targeting AURKA in pancreatic cancer. Additionally, instability [61]. These studies, as well as other studies, AURKA can phosphorylate RalA at Ser194 and regulate focused mainly on the fact that overexpression of AURKA its subcellular localization, which is essential for Ras-

Katsha et al. Molecular Cancer (2015) 14:106

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mediated cellular transformation [74]. However, further The first generation MLN8054 was terminated in phase studies by the same group failed to show correlation of 1 clinical trials due to off-target toxicities [86]. Both RalA (S194) phosphorylation with responsiveness to drugs are ATP competitive, where they bind and inhibit MLN8237, indicating that the principal target of AURKA AURKA phosphorylation at T288. In murine xenograft

  • may not be RalA [75].
  • models, MLN8237 was well tolerated with doses ran-

ging from 15 to 40 mg/kg/d. MLN8237 was also found to be well absorbed and steady state plasma levels were

AURKA in liver cancer

In human hepatocellular carcinoma (HCC), AURKA was reached within 7 days of twice daily dosing in phase 1 found to be overexpressed at mRNA level in 61% of clinical trials [87]. Investigations of MLN8237 in HCC samples [30], whereas gene amplification was re- preclinical studies have shown that it induces abnormal corded in only 3 out of 224 HCC samples [30]. Notably, G2/M cell cycle arrest, abnormalities in mitotic spinhigh expression levels of AURKA were associated with dles, and apoptosis in upper GI cancers [48,49,53]. In high-grade, high-stage tumors and poor outcome. Micro- addition, MLN8237 down-regulates several oncogenic array studies suggested that AURKA phosphorylates pathways such as NF-κB [49,88], AKT [19], and STAT3 and stabilizes hepatoma up-regulated protein (HURP) [55] in cancer cells. On the other hand, several reports [76], a cell cycle regulated gene that is overexpressed in demonstrated that treatment with MLN8237 could actihuman hepatocellular carcinoma (HCC) [77]. On the vate p53 [47,48,89] and p73 [52,56] apoptotic pathways. other hand, it was reported that hypoxia and hypoxia- The effects of MLN8237 were tested in several non-GI inducible factor-1 (HIF-1) are important in the tumor cancers. It has been shown that MLN8237 sensitized microenvironment and could regulate AURKA at the PC3 and DU145 prostate cancer cells to radiation, intranscriptional level [78,79]. Other studies showed that creased the DNA double-strand breaks, induced G2/M AURKA, can in turn, regulate HIF-1α through activa- cell cycle arrest and polyploidy [90]. Treatment of tion of AKT and p38-MAPK signaling pathways leading OVCAR-5 and SKOV3ip2 ovarian cancer cells with to malignant phenotypes of HCC [80], indicating a posi- MLN8237 resulted in inhibition of cytoskeletal regulative feedback loop sustaining continuous activation of tory SRC (assessed by decreased phosphorylation at AURKA. Several preclinical studies investigated the ef- Tyr-416) and decreased migration and adhesion [18]. fects of AURKA inhibition in HCC. For example, a re- Moreover, MLN8237 has been tested on many pediatric port showed that the pan Aurora inhibitor PHA-739358 cancer cell lines like Ewing sarcoma, neuroblastoma, inhibits HCC tumor growth in a tumor xenograft mouse glioblastoma, rhabdomyosarcoma, ALL, and AML where model [81]. Further, AURKA inhibition with small mol- it inhibited cell growth and delayed tumor growth [91]. In ecule R1498 was found to target mitosis pathway and vitro and in vivo tumor xenografts mouse models showed suppress angiogenesis [82]. These studies emphasize the that MLN8237 enhances anti-tumor activity of chemomultifaceted roles of AURKA in HCC and imply therapeutics. For instance, dual treatment of MLN8237

  • AURKA as a feasible druggable target in HCC.
  • with Docetaxel enhanced apoptosis and anti-tumor activ-

ity in lymphoma [92] and UGI adenocarcinomas cell models [53]. Similarly, a combination of Cisplatin with

Clinical development of aurora kinase A inhibitors

The aforementioned preclinical studies shed light on the MLN8237 had robust anti-tumor activity in tumor xenoroles and contributions of AURKA in tumorigenesis, graft models of esophageal adenocarcinomas [57]. In B- which serve as premise for the development of several cell Non-Hodgkin Lymphoma, MLN8237 in combination pan Aurora kinase inhibitors (AKIs) and selective inhibi- with Vincristine and Rituximab showed robust cell death tors of AURKA. In the following section, we will focus in vitro and had curative effects in vivo using mantle cell on the present investigational AURKA inhibitors in com- lymphoma (MCL) mouse xenograft model [93]. Collect-

  • pleted, ongoing, or planned clinical trials.
  • ively, the present data indicate that MLN8237 is an effect-

ive drug with high specificity and limited off target activity that works in various models. Notably, there are 49 clin-

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  • The Aurora B Kinase Activity Is Required for the Maintenance of the Differentiated State of Murine Myoblasts

    The Aurora B Kinase Activity Is Required for the Maintenance of the Differentiated State of Murine Myoblasts

    Cell Death and Differentiation (2009) 16, 321–330 & 2009 Macmillan Publishers Limited All rights reserved 1350-9047/09 $32.00 www.nature.com/cdd The Aurora B kinase activity is required for the maintenance of the differentiated state of murine myoblasts G Amabile1,2, AM D’Alise1, M Iovino1, P Jones3, S Santaguida4, A Musacchio4, S Taylor5 and R Cortese*,1 Reversine is a synthetic molecule capable of inducing dedifferentiation of C2C12, a murine myoblast cell line, into multipotent progenitor cells, which can be redirected to differentiate in nonmuscle cell types under appropriate conditions. Reversine is also a potent inhibitor of Aurora B, a protein kinase required for mitotic chromosome segregation, spindle checkpoint function, cytokinesis and histone H3 phosphorylation, raising the possibility that the dedifferentiation capability of reversine is mediated through the inhibition of Aurora B. Indeed, here we show that several other well-characterized Aurora B inhibitors are capable of dedifferentiating C2C12 myoblasts. Significantly, expressing drug-resistant Aurora B mutants, which are insensitive to reversine block the dedifferentiation process, indicating that Aurora B kinase activity is required to maintain the differentiated state. We show that the inhibition of the spindle checkpoint or cytokinesis per se is not sufficient for dedifferentiation. Rather, our data support a model whereby changes in histone H3 phosphorylation result in chromatin remodeling, which in turn restores the multipotent state. Cell Death and Differentiation (2009) 16, 321–330; doi:10.1038/cdd.2008.156; published online 31 October 2008 Lineage-restricted cells can be reprogramed to a state Evidence is emerging that the role of Aurora B is not of pluripotency by several different manipulations, including restricted to mitosis and cell division.
  • Ncomms4885.Pdf

    Ncomms4885.Pdf

    ARTICLE Received 4 Feb 2014 | Accepted 14 Apr 2014 | Published 30 May 2014 DOI: 10.1038/ncomms4885 Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size Jian-Fu Chen1,2, Ying Zhang1, Jonathan Wilde1, Kirk C. Hansen3, Fan Lai4 & Lee Niswander1 Human genetic studies have established a link between a class of centrosome proteins and microcephaly. Current studies of microcephaly focus on defective centrosome/spindle orientation. Mutations in WDR62 are associated with microcephaly and other cortical abnormalities in humans. Here we create a mouse model of Wdr62 deficiency and find that the mice exhibit reduced brain size due to decreased neural progenitor cells (NPCs). Wdr62 depleted cells show spindle instability, spindle assembly checkpoint (SAC) activation, mitotic arrest and cell death. Mechanistically, Wdr62 associates and genetically interacts with Aurora A to regulate spindle formation, mitotic progression and brain size. Our results suggest that Wdr62 interacts with Aurora A to control mitotic progression, and loss of these interactions leads to mitotic delay and cell death of NPCs, which could be a potential cause of human microcephaly. 1 Howard Hughes Medical Institute, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Children’s Hospital Colorado, Aurora, Colorado 80045, USA. 2 Department of Genetics, Department of Biochemistry & Molecular Biology, University of Georgia, Athens, Georgia 30602, USA. 3 Biochemistry & Molecular Genetics, University of Colorado Denver, Aurora, Colorado 80045, USA. 4 The Wistar Institute, 3601 Spruce Street, Philadelphia, Pennsylvania 19104, USA. Correspondence and requests for materials should be addressed to J-F.C. (email: [email protected]) or to L.N.
  • Covalent Aurora a Regulation by the Metabolic Integrator Coenzyme A

    Covalent Aurora a Regulation by the Metabolic Integrator Coenzyme A

    bioRxiv preprint doi: https://doi.org/10.1101/469585; this version posted November 14, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-ND 4.0 International license. Covalent Aurora A regulation by the metabolic integrator coenzyme A Yugo Tsuchiya1#, Dominic P Byrne2#, Selena G Burgess3#, Jenny Bormann4, Jovana Bakovic1, Yueyan Huang1, Alexander Zhyvoloup1, Sew Peak-Chew5, Trang Tran6, Fiona Bellany6, Alethea Tabor6, AW Edith Chan7, Lalitha Guruprasad8, Oleg Garifulin9, Valeriy Filonenko9, Samantha Ferries10, Claire E Eyers10, John Carroll4^, Mark Skehel5, Richard Bayliss3*, Patrick A Eyers2* and Ivan Gout1,9* 1Department of Structural and Molecular Biology, University College London, London WC1E 6BT, UK 2Department of Biochemistry, Institute of Integrative Biology, University of Liverpool, Liverpool L69 7ZB, UK 3School of Molecular and Cellular Biology, Astbury Centre for Structural and Molecular Biology, University of Leeds, Leeds LS2 9JT, UK 4Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK 5MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK 6Department of Chemistry, University College London, London WC1E 6BT, UK 7Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK 8School of Chemistry, University of Hyderabad, Hyderabad 500 046, India 9Department of Cell
  • Quantitative Conformational Profiling of Kinase Inhibitors Reveals Origins of Selectivity for Aurora Kinase Activation States

    Quantitative Conformational Profiling of Kinase Inhibitors Reveals Origins of Selectivity for Aurora Kinase Activation States

    Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states Eric W. Lakea, Joseph M. Murettab, Andrew R. Thompsonb, Damien M. Rasmussenb, Abir Majumdara, Erik B. Faberc, Emily F. Ruffa, David D. Thomasb, and Nicholas M. Levinsona,d,1 aDepartment of Pharmacology, University of Minnesota, Minneapolis, MN 55455; bDepartment of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455; cDepartment of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455; and dMasonic Cancer Center, University of Minnesota, Minneapolis, MN 55455 Edited by Kevan M. Shokat, University of California, San Francisco, CA, and approved November 7, 2018 (received for review June 28, 2018) Protein kinases undergo large-scale structural changes that tightly lytically important Asp–Phe–Gly (DFG) motif, located on the regulate function and control recognition by small-molecule in- flexible activation loop of the kinase, is flipped relative to its hibitors. Methods for quantifying the conformational effects of orientation in the active state (referred to as “DFG-out,” in inhibitors and linking them to an understanding of selectivity contrast to the active “DFG-in” state). The observation that the patterns have long been elusive. We have developed an ultrafast inactive DFG-out states of kinases are more divergent than the time-resolved fluorescence methodology that tracks structural catalytically competent DFG-in state has led to a focus on type II movements of the kinase activation loop in solution with inhibitors as a potential answer to the selectivity problem (8, 9). angstrom-level precision, and can resolve multiple structural states However, kinome-wide profiling of kinase inhibitors has revealed and quantify conformational shifts between states.
  • Kinase-Targeted Cancer Therapies: Progress, Challenges and Future Directions Khushwant S

    Kinase-Targeted Cancer Therapies: Progress, Challenges and Future Directions Khushwant S

    Bhullar et al. Molecular Cancer (2018) 17:48 https://doi.org/10.1186/s12943-018-0804-2 REVIEW Open Access Kinase-targeted cancer therapies: progress, challenges and future directions Khushwant S. Bhullar1, Naiara Orrego Lagarón2, Eileen M. McGowan3, Indu Parmar4, Amitabh Jha5, Basil P. Hubbard1 and H. P. Vasantha Rupasinghe6,7* Abstract The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein- coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies. Keywords: Kinases, Kinase inhibition, Small-molecule drugs, Cancer, Oncology Background Recent advances in our understanding of the fundamen- Kinases are enzymes that transfer a phosphate group to a tal molecular mechanisms underlying cancer cell signaling protein while phosphatases remove a phosphate group have elucidated a crucial role for kinases in the carcino- from protein.
  • Functional Interplay Between NF-Κb-Inducing Kinase and C-Abl

    Functional Interplay Between NF-Κb-Inducing Kinase and C-Abl

    Plasma Cell Disorders ARTICLE Functional interplay between NF- B-inducing kinase and c-Abl kinases limits responseκ to Ferrata Storti Foundation Aurora inhibitors in multiple myeloma Laura Mazzera,1,2 Manuela Abeltino,1 Guerino Lombardi,2 Anna Maria Cantoni,3 Roberto Ria,4 Micaela Ricca,2 Ilaria Saltarella,4 Valeria Naponelli,1 Federica Maria Angela Rizzi,1,5 Roberto Perris,5,6 Attilio Corradi,3 Angelo Vacca,4 Antonio Bonati1,5 and Paolo Lunghi5,6 1 2 Department of Medicine and Surgery, University of Parma, Parma; Istituto Zooprofilattico Haematologica 2019 Sperimentale della Lombardia e dell’Emilia Romagna “Bruno Ubertini,” Brescia; 3Department of Veterinary Science, University of Parma, Parma; 4Department of Volume 104(12):2465-2481 Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari "Aldo Moro" Medical School, Bari; 5Center for Molecular and Translational Oncology, University of Parma, Parma and 6Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy ABSTRACT onsidering that Aurora kinase inhibitors are currently under clinical investigation in hematologic cancers, the identification of molecular Cevents that limit the response to such agents is essential for enhanc- ing clinical outcomes. Here, we discover a NF-κB-inducing kinase (NIK)-c- Abl-STAT3 signaling-centered feedback loop that restrains the efficacy of Aurora inhibitors in multiple myeloma. Mechanistically, we demonstrate that Aurora inhibition promotes NIK protein stabilization via downregula- tion of its negative regulator TRAF2. Accumulated NIK converts c-Abl tyro- sine kinase from a nuclear proapoptotic into a cytoplasmic antiapoptotic effector by inducing its phosphorylation at Thr735, Tyr245 and Tyr412 residues, and, by entering into a trimeric complex formation with c-Abl and Correspondence: STAT3, increases both the transcriptional activity of STAT3 and expression PAOLO LUNGHI of the antiapoptotic STAT3 target genes PIM1 and PIM2.