The Relevance of Aurora Kinase Inhibition in Hematological Malignancies
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CANCER DIAGNOSIS & PROGNOSIS
1: 111-126 (2021) doi: 10.21873/cdp.10016
Review
The Relevance of Aurora Kinase Inhibition
in Hematological Malignancies
CAIO BEZERRA MACHADO*, EMERSON LUCENA DA SILVA*, BEATRIZ MARIA DIAS NOGUEIRA,
JEAN BRENO SILVEIRA DA SILVA, MANOEL ODORICO DE MORAES FILHO,
RAQUEL CARVALHO MONTENEGRO, MARIA ELISABETE AMARAL DE MORAES
and CAROLINE AQUINO MOREIRA-NUNES
Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM),
Federal University of Ceará, Fortaleza, CE, Brazil
Abstract. Aurora kinases are a family of serine/threonine In 2017 alone, nearly 24.5 million new cases of cancer
protein kinases that play a central role in eukaryotic cell were diagnosed worldwide, and more than 9.5 million
division. Overexpression of aurora kinases in cancer and people died from the disease. Cancer can be described as a
their role as major regulators of the cell cycle quickly heterogeneous set of diseases that share the main clinical
inspired the idea that their inhibition might be a potential characteristic of uncontrolled cell proliferation in the form
pathway when treating oncologic patients. Over the past of a solid tumor or as individual cells in the bloodstream
couple of decades, the search for designing and testing of (1, 2).
molecules capable of inhibiting aurora activities fueled many Even though cancer is characterized as a multifactorial
pre-clinical and clinical studies. In this study, data from the disease, the accumulation of genetic mutations, as well as the
past 10 years of in vitro and in vivo investigations, as well deregulation of the cellular cycle, are both well-established
as clinical trials, utilizing aurora kinase inhibitors as occurrences in cancerous cells. Failure in the regulation of
therapeutics for hematological malignancies were compiled the cell cycle is associated with malignant neoplasms since
and discussed, aiming to highlight potential uses of these it is fundamental for genome maintenance, repairing DNA
inhibitors as a novel monotherapy model or alongside damage and, consequently, preventing the proliferation of
conventional chemotherapies. While there is still much to be cells with malignant potential (3, 4).
elucidated, it is clear that these kinases play a key role in As one of the main factors in cell-cycle control, the
oncogenesis, and their manageable toxicity and potentially activity of protein kinases is to be highlighted due to their
synergistic effects still render them a focus of interest for vital roles in several phases of cell division. In recent years,
future investigations in combinatorial clinical trials it has been demonstrated that alterations in cellular
expression levels of many kinases are associated with
malignant cancer phenotypes, pointing them out as possible
therapeutic targets for these diseases. One such kinase family
This article is freely accessible online.
of possible clinical relevance are the aurora kinases (5, 6).
*These Authors contributed equally to this work.
Role of Aurora Kinases in Cell Division
Correspondence to: Caroline Aquino Moreira-Nunes, Federal
University of Ceará, Coronel Nunes de Melo st, n 1000, Rodolfo The aurora kinases are a family of serine/threonine protein
Teófilo, CEP: 60416-000 Fortaleza, CE, Brazil. Tel: +55 kinases that play a central role in eukaryotic cell division.
8533668033, e-mail: carolfam@gmail.com
Humans express three different types of aurora kinases:
Key Words: Hematological neoplasms, aurora kinases, targeted aurora kinase A (AURKA), aurora kinase B (AURKB) and
molecular therapy, review. aurora kinase C (AURKC). AURKA and AURKB are the
most relevant to mitosis, being expressed in most somatic
©2021 International Institute of Anticancer Resarch cell types, while AURKC is mostly expressed in germ cells
www.iiar-anticancer.org due to its role in meiosis regulation (7, 8).
111
CANCER DIAGNOSIS & PROGNOSIS 1: 111-126 (2021)
From the first reports of them being essential in cell AURKB
division to the recent years of thorough molecular studies,
the auroras have been described as oncogenes relevant to Along with the regulatory proteins inner centromere protein,
many human malignancies (9, 10). Their gene amplification survivin and borealin, AURKB forms the chromosomal
and overexpression is detected particularly in solid tumors, passenger complex (CPC) and takes part in regulating crucial
however, their correlation with leukemia development has pathways for chromosome condensation, sister chromatid
also been reported (10, 11). separation and cytokinesis (30).
The family name as aurora was conceived when it was During the G2 phase, at mitosis onset, AURKB is
first discovered that aurora-mutated Drosophila cells failed responsible for phosphorylation of histone H3 (Figure 2), an
to properly duplicate and separate their centrosomes during event that coincides with heterochromatin condensation and
mitosis, inducing the formation of monopolar spindles that, proper chromosome formation (31-33). In vitro experiments
when observed under a microscope, would bear resemblance utilizing analogous animal models have demonstrated AURKA
to the aurora borealis phenomenon (12). Later studies led to to be a better kinase for the phosphorylation of H3 than
the determination of the localization of these kinases (Figure AURKB, however, the intracellular colocalization of AURKB
1) and their actual cellular roles in humans. and phosphorylated H3, and the knowledge that a decrease in
AURKB level implicates in reduced H3 phosphorylation, leads
AURKA to the understanding that in vivo models favor AURKB activity
for histone phosphorylation (33, 34).
Prior to bipolar spindle formation, from late S phase to pro- After chromosome condensation, during prophase in early
metaphase, AURKA is mainly concentrated at centrosomes (13, mitosis, the activation of phosphorylated histones H3 and
14) due to an increase in cyclin-dependent kinase 11 (CDK11) H2A recruits AURKB to the centromeres (35-37). It has been
activity (15). AURKA is then a part of important processes for suggested that recruitment of AURKB happens in a two-step
centrosome maturation such as pericentriolar matrix recruitment process where H2A phosphorylation by BUB1 mitotic
and microtubule nucleation and stabilization (16, 17). checkpoint serine/threonine protein kinase (BUB1) firstly
The role of AURKA in maturation occurs through creates a pool of kinetochore-bound AURKB and then H3
phosphorylation loops and protein-protein interactions with phosphorylation by haspin kinase translocates this AURKB
many different kinases. One such pathway is AURKA- pool to the inner centromere, where it is mainly located
mediated phosphorylation of a large tumor suppressor 2 during prophase (38).
(LATS2) and ajuba LIM protein (AJUBA) complex which Until the onset of anaphase, AURKB phosphorylation of
acts on an auto-phosphorylation loop that directs AURKA to the KMN network, an association of the conserved
the centrosomes and induces the recruitment of a kinetochore proteins kinetochore null protein 1 (KNL1), mis-
centrosomal pool of γ-tubulin, an essential step for segregation 12 (MIS12) and nuclear division cycle 80
microtubule nucleation and later spindle assembly (17-20). (NDC80), takes part in regulating kinetochore-microtubule
During metaphase and throughout mitosis, the bipolar attachment stabilization (39, 40). While during early mitosis
spindle assembly begins and AURKA also localizes to spindle the attachment turnover is high, ensuring quickly
microtubules, as well as the centrosomes (21, 22). AURKA destabilization of incorrect attachments, it tends to slow
localization to spindle microtubules is dependent on activity down alongside mitosis progression after correct and stable
of TPX2 microtubule nucleation factor (TPX2) which binds attachments are formed and the spindle assembly checkpoint
to and activates AURKA at the spindles, inhibiting is satisfied, allowing for increased activity of anaphase-
dephosphorylation by protein phosphatase 1 (PP1) (22-24). promoting complex/cyclosome and proper chromosomal
Aurora-related proteins have been shown to phosphorylate separation in anaphase (38, 40-42).
kinesin family member 11 (EG5), an important microtubule- AURKB also exerts major roles in cytokinesis, from initial
motor protein responsible for centrosome separation, in the anaphase through telophase and the end of mitosis, being
Xenopus laevis model, thus conferring it a major role in relocated from inner centromeres to the spindle midzone by
bipolar spindle formation (25, 26). However, it has been the action of mitotic kinesin MKLP2 and then interacting with
demonstrated that AURKA is also involved in EG5- kinesins KIF4A and KIF2A to promote microtubule bundling
independent pathways for bipolar spindle assembly through and consequent central spindle formation, as well as proper
phosphorylation of another motor protein, kinesin-12 cleavage furrow completion (43-45). It has been shown that
(KIF15/HKLP2), in human cell models (27, 28). after chromosomaI segregation, the activity of AURKB at the
Besides its role in cellular spatial organization, AURKA spindle midzone functions as a checkpoint for the regulation
also exerts a series of nuclear functions related to the control of incorrectly segregated chromatin, inhibiting the formation
of mitotic checkpoint G2/M (Figure 2), making it a key of tetraploid daughter cells and protecting lagging
factor in initiation of mitosis (20, 29). chromosomes from breakage (45, 46).
112Machado et al: Aurora Kinases in Hematological Malignancies (Review)
Figure 1. Aurora A (AURKA) and aurora B (AURKB) localization throughout mitosis. Representation of the localization of aurora kinases and their
interactions in cell division. The main interactions of AURKA revolve around centrosomes and microtubule nucleation and stabilization, while
AURKB acts upon proper sister chromatid separation and cytokinesis.
Figure 2. Nuclear roles of aurora kinase A (AURKA) and aurora kinase B (AURKB). AURKA auto-activates and phosphorylates BORA aurora
kinase A activator (BORA), which acts as a cofactor and enhances AURKA activity. Polo-like kinase 1 (PLK1) is also phosphorylated by AURKA
and then acts upon WEE1 G2 checkpoint kinase (WEE1), a kinase responsible for the inhibition of the cyclin-dependent kinase 1 (CDK1)–cyclin B
complex, allowing initiation of mitosis through unlocking of the G2/M checkpoint. After WEE1 activation, PLK1 promotes BORA degradation and
mitosis continuation. AURKB interacts with inner centromere protein (INCEP), survivin and borealin to form mitotic regulator machinery, the
chromosomal passenger complex (CPC). AURKB phosphorylates histone H3 (HisH3) and allows chromatin reorganization in mitosis. Both AURKA
and AURKB undergo ubiquitination and are degraded at the end of mitosis (20, 29, 33).
AURKC its ability to interact with chromosomal passenger complex
proteins has led to the understanding that AURKC exerts many
The activity and metabolic role of AURKC is still poorly functions that overlap with activities of AURKB in meiotic cells,
understood when compared to the other two aurora kinases being responsible for the regulation of kinetochore-microtubule
expressed by humans, being mostly described by its overlapping attachment and proper sister chromatid segregation (48, 49).
functions with AURKB (47, 48). Although poorly expressed in AURKC has also been observed to be highly expressed in
most somatic cells, high AURKC expression in germ cells and pre-implantation embryo cells, being able to carry out
113CANCER DIAGNOSIS & PROGNOSIS 1: 111-126 (2021)
normal cell division in AURKB-null mice with death associated with abnormal segregation, resulting in polyploid
occurring only after implantation takes place, making it clear cells (34). Otherwise, cells lacking both genes are able to
that AURKC may be relevant in the division of somatic cells finish mitosis without completing anaphase, resulting in
(50, 51). While the non-overlapping functions of AURKB polyploid cells with just one nucleus (72).
and AURKC are not fully elucidated, both kinases are known Most studies evaluating the mechanism of AKI action in
to form distinct complexes with chromosomal passenger hematologic cell lines focus on acute myeloid leukemia
complex proteins and act through distinct mechanisms, while (AML). This neoplasia is characterized by clonal expansion
still being able to interfere with each other’s activities, as of undifferentiated myeloid precursors, leading to impaired
shown by experiments of selective inhibition of one or both hematopoiesis and bone marrow failure (73). In in vitro
kinases (52). studies, AKIs were evaluated alone or in combination with
cytarabine, a nucleoside analog that is incorporated into
Aurora Family as Targets in DNA in cell replication (S-phase) (74). The synergism of
Oncohematological Therapy cytarabine with pan-AKI AMG 900 enhanced the
antileukemic effect and attenuated polyploidization (60). In
The finding of overexpression of aurora kinases in cancer and another study, the AURKB inhibitor barasertib used in
their role as major regulators of the cell cycle quickly led to combination with cytarabine showed a greater-than-additive
the idea that their inhibition might be a potential pathway cytotoxic effect with evidence of apoptosis, since barasertib
when treating oncological patients. Over the past couple of does not prevent DNA synthesis, enabling cytarabine
decades, the quest to design and test molecules capable of incorporation into DNA (66).
inhibiting aurora activities fueled many pre-clinical and Internal tandem duplication of FMS-like receptor tyrosine
clinical studies, resulting in the development of a series of kinase 3 (FLT3) is one of the most common somatic
pan-aurora inhibitors as well as selective inhibitors of one of mutations characterized in AML. It results in the constant
the three human kinases (53). While some aurora kinase activation of FLT3 kinase, which is linked to cancer
inhibitors (AKIs) demonstrate promising results as single resurgence and poor patient survival (75). The dual FLT3
treatments, it is also important to perceive their potential as inhibitor/AKI CCT241736 showed promising antileukemic
synergistic compounds, being able to restore sensitivity to effect in vitro and in vivo, as well as in primary samples
chemotherapy agents in tumor cells and interact with other from patients with AML, including those who were resistant
targeted therapies for increased efficacy (54). to the FLT3 inhibitor quizatinib, indicating that dual
In this scenario, hematological malignant disorders as inhibition can be a tool to manage therapies in patients with
leukemia presents overexpression of AURK, and the use of AML presenting internal tandem duplication of FLT3 with
AKIs seems to be an effective pharmacological approach to resistance to current chemotherapy (56).
treating these diseases (14). Table I presents studies Translocation t(8;21) is frequent in 4-8% of patients with
published in the past 10 years describing the mechanism of AML and results in the chimeric protein RUNX family
action of several AKIs in different leukemia cell lines, as transcription factor 1-RUNX1 partner transcriptional co-
well as in in vivo models, and validation of AURKA and B repressor 1 (RUNX1-RUNX1T1); 40-60% of patients
overexpression in patient samples. The studies showed that harboring this translocation are susceptible to relapse after
the antileukemic effect of AKI AURKA and AURKB are complete remission, this being one of the major causes of
consistently related to G2/M cell-cycle arrest, modulation of treatment failure (76-78). Qi et al. showed that AURKB
the expression of cell cycle regulators, and polyploidy inhibitor barasertib was more successful in inhibiting
induction resulting in apoptotic cell death. proliferation of AML cell lines with t(8;21) than cytarabine
AURKA and AURKB have an important role in cell-cycle and AURKA inhibitor alisertib, and combination of the two
progression, in fact, the transcription of AURK is cell cycle- AKIs did not show a synergistic effect, indicating that
regulated. AURKA mRNA is found at higher concentrations AURKB inhibitor may be a more efficient inhibitor in the
in the G2/M phase, its protein level reaching higher a little treatment of patients with a specific subtype of AML (58).
later; the same happens to AURKB, with enhanced levels of Acute lymphoblastic leukemia (ALL) is the most common
mRNA and protein expression just after those of AURKA leukemia diagnosed in adults and the second most frequent
(14). Inhibition of AURKA expression by genetic knockdown acute subtype in children worldwide, this neoplasia presents
was shown to lead to errors in cell mitotic processes, once chromosomal and genetic alterations related to the
the spindle checkpoint detects a failure in chromosome differentiation and proliferation of T and B precursor cells
alignment, it culminates in mitotic arrest and cellular death (79, 80). AURKA and AURKB are overexpressed in samples
by apoptosis (71). The knockdown of AURKB leads to from patients with ALL (55, 65, 81) and some research
reduction in histone H3 phosphorylation required in described the mechanism of action of AKI in ALL cell lines
chromosome condensation and cytokinesis, these errors are alone or in combination with other antineoplastics agents.
114Machado et al: Aurora Kinases in Hematological Malignancies (Review)
Genetic alterations as t(4;11) with mixed lineage leukemia without BCR–ABL1T315I mutation, and also in ALL Ph− cell
(MLL) fusion–associated gene AF4 (MLL-AF4) and t(9;22) lines. Danusertib induced cytotoxicity in all cells
with breakpoint cluster region–Abelson murine leukemia 1 independently of BCR–ABL1T315I mutation and Ph presence,
(BCR–ABL1) are frequent in ALL and are related to treatment as well as reducing the percentage of leukemia cells
resistance, poor outcome, and disease relapse (65, 82). (CD10+/CD19+) and enhancing the survival rates of mice
Rearrangements of MLL gene represents 10% of ALL cases transplanted with cells with BCR–ABL1T315I mutation (67).
and MLL–AF4 fusion is present in the majority of ALL cases The study also attested to synergism in the cytotoxic effect
(57%), is highly associated with rapid cancer development, of the pan-AKI danusertib in combination with
fast progression, and poor prognosis in comparison with farnesyltransferase inhibitor, vincristine, and with the TKI
patients without this rearrangement (83, 84). dasatinib independently of BCR–ABL1T315I mutation,
In in vitro studies evaluating the cytotoxicity of the pan- suggesting danusertib as a new option for chemotherapy in
AKIs VX-680 and VE-465 against a panel of ALL cell lines, patients with ALL, since it is effective independently of Ph
cell lines with MLL–AF4 fusion showed higher sensitivity to presence or BCR–ABL1T315I mutation, and, especially for
AKI treatment, and VE-465 gave better results when patients with BCR–ABL1T315I mutation who are resistant to
compared to VX-68. Curiously, the same study reported that actual treatment with TKIs.
these cell lines presented AURKB protein expression higher CML is basically, but not only, characterized by the
than AURKA (65). A recent study conducted by Moreira- presence of Ph+ cells, since around 95% of cases present this
Nunes et al. observed no difference between AURKA and translocation (94, 95). Thus, the malignant potential of CML
AURKB gene expression in samples with MLL–AF4 fusion cells is related to the BCR–ABL1 chimeric gene, which is
from patients with ALL when compared to other frequent also its pharmacologic target (85, 96). Resistance to TKIs in
fusions in leukemia [BCR–ABL1, transcription factor 3 (E2A CML is widely documented and occurs in 20-40% of cases
immunoglobulin enhancer-binding factors E12/E47) and pre- (97), furthermore, the overexpression of AURKA in several
B-cell leukemia transcription factor 1 (E2A–PBX1) cancer types is described as one mechanism of
translocation, stem leukemia cell interrupting locus and T- chemoresistance (98-104).
cell acute lymphocytic leukemia protein 1 (SIL–TAL1) In vitro studies monitored the antileukemia effect of pan-
fusion, translocation–Ets–leukemia and acute myeloid AKIs GW809897X and GW806742X in a non-resistant
leukemia 1 protein (TEL–AML1) fusion]. In contrast, when CML cell line, with promising results (55). Long et al.
the expression of AUKA and B were analyzed in all patients showed that AURKA inhibitor AKI603 suppressed cell
in the study, AURKB expression was higher than that of growth and induced cell differentiation of both imatinib-
AURKA and overexpression was correlated with lower resistant (BCR–ABL1T315I) and non-resistant cell lines (64).
survival rates (55). Thus, due to the role of AURKB in ALL, A similar study showed that AURKA inhibitor alisertib,
and even the lack of evidence that correlates the expression when used alone, reduced viability of CML cell lines, both
of this kinase with outcome in those with MLL–AF4, more non-resistant and resistant to imatinib and nilotinib, as well
studies evaluating AURKB inhibitors in therapy of MLL– as cells harboring BCR–ABL1T315I mutations. Moreover,
AF4 ALL are still necessary. when administered in combination with the TKIs imatinib,
The Philadelphia chromosome (Ph+) is characterized by ponatinib or nilotinib, there was a disruption in the resistance
the translocation between chromosomes 9 and 22, generating mechanism and reduced rates of cell growth were observed
the chimeric gene BCR–ABL1 (85, 86). Although this in the respective resistant cell lines. Moreover, alisertib plus
translocation is more described in chronic myeloid leukemia ponatinib showed an additive effect in reducing tumor
(CML), the presence of Ph affects around 3-5% of children volume and enhanced the rate of survival in mice
and 25% of adults with ALL, and is related to a poor transplanted with CML BCR–ABL1T315I+ cells (61).
prognosis (87-89). The chimeric BCR–ABL1 gene is Inhibition of AURKA seems to reduce the profile of
constitutively active and overexpresses a tyrosine-kinase resistance in CML cell lines in vitro and in vivo; the
receptor that is involved in signaling pathways linked to utilization of AKIs in combination with conventional
cellular proliferation, de-differentiation, and apoptosis escape chemotherapy may improve the outcome of patients that are
(90). Although tyrosine-kinase inhibitors (TKIs) such as unresponsive to chemotherapy for CML.
imatinib, bosutinib, dasatinib, and nilotinib were developed, Lymphomas are a group of malignant diseases that can be
mutations in catalytic enzymatic domains as ABL1T315I result derived from constituent cells of the lymphoid tissue,
in TKI resistance, leading to risk of treatment failure in lymphocytes and histiocytes. Malignant lymphomas are
patients with CML or ALL Ph+ (67, 91-93). divided into Hodgkin’s and non-Hodgkin’s lymphoma
Due to the efficacy of AKIs in leukemia cell lines in vitro (NHL) and are more common in the head and neck region,
and in in vivo studies, Fei et al. evaluated the pan-AKI but NHL can also be found in extranodal regions (25% of
danusertib (PHA-739358) in human ALL cell lines with and the cases), with or without lymph node involvement. NHL is
115CANCER DIAGNOSIS & PROGNOSIS 1: 111-126 (2021)
Table I. In vitro studies utilizing Aurora-kinase inhibitors as a monotherapy or in combination with synergetic treatments in the past 10 years.
Kinase Study Leukemia Cell Genetic alterations Aurora Synergistic Mechanism Reference
assessed phase subtype line assessed inhibitor treatment
AURKA/B/C In vitro with ALL K-562 BRC–ABL1 GW809897X NR Cell death 55
validation in CML E2A–PBX GW806742X Caspase 3 and 7 activation
patient samples MLL–AF4 G2/M cell-cycle arrest
SIL–TAL
EL–AML1
AURKA/B/C In vitro, in vivo AML MOLM-13 FLT3–ITD CCT241736 NR Reduced viability 56
with validation MV4-11 Apoptosis
in patient G2/M cell-cycle arrest
samples Reduces phosphorylation
of FLT3, STAT5,
MAPK and AURKA/B
Reduced tumor growth
and STAT5 and AURKA
phosphorylation
AURKA In vitro and AML HL-60 NR AKI604 NR Inhibition of proliferation 57
in vivo U937 and colony formation
Mitochondrial impairment
Elevation of ROS as well as
cellular calcium (Ca2+) levels
Increase in polyploid cells
Inhibition of tumor growth
AURKA/B/C In vitro AML Kasumi-1 RUNX1– Alisertib NR Reduction in proliferation 58
Skno-1 RUNX1T1 (MLN8237) G2/M cell-cycle arrest
Barasertib Modulation in the expression
(AZD1152-HQPA) of cell cycle regulators
AURKA In vitro AML Kasumi-1 NR Radotinib NR Cytotoxicity 59
Reduced expression of
cyclin-dependent
kinase 1 and cyclin B1
Reduced phosphorylation
of AURKA
G2/M cell cycle arrest
AURKA/B/C In vitro AML MOLM-13 FLT3–ITD AMG 900 Cytarabine Reduction in proliferation 60
MV-411 TP53 Induces polyploidization
KG-1 P–gp and apoptosis
MEGAL
U937
HEL
CHRF-288-11
AURKA In vitro and CML K-562 BRC–ABL1 Alisertib Imatinib and Blocked cell proliferation 61
in vivo Ba/F3 BRC– (MLN8237) Ponatinib Apoptosis
K-562/IR ABL1T315I AURKA phosphorylation
K-562/NILR G2/M cell cycle arrest
Enhanced ROS levels
Reduced tumor growth
AURKA In vitro NHL DOHH2 MYC Alisertib ABT-199 Suppressed cell growth 62
(DHL) VAL BCL2 (MLN8237) G2/M cell cycle arrest
Apoptosis
Enhanced expression of cell
intrinsic apoptotic proteins
Reduction in AURKA
phosphorylation and
MYC expression
Table I. Continued
116Machado et al: Aurora Kinases in Hematological Malignancies (Review)
Table I. Continued
Kinase Study Leukemia Cell Genetic alterations Aurora Synergistic Mechanism Reference
assessed phase subtype line assessed inhibitor treatment
AURKB In vivo AML HL-60 FLT3–ITD Barasertib Cytarabine Inhibited tumor growth 63
OCI-AML3 (AZD1152- Increased phospho-histone
MV4-11 HQPA) H3 inhibition, polyploidy,
MOLM-13 and tumor cell apoptosis
AURKA In vitro CML KBM-5 BRC–ABL1 AKI603 NR Reduced cell viability 64
KBM-5T315I BRC– Inhibited phosphorylation
ABL1T315I of AURKA at Thr288
G2/M cell-cycle arrest with
polyploidy accumulation
Apoptosis
AURKA/B/C In vitro with ALL RS4;11 MLL–AF4 VE-465 NR Cytotoxicity 65
validation in MV4;11 TP53 VX-680 Inhibition of AURKA
patient samples CCRF-SB phosphorylation
MOLT-3 G2/M cell-cycle arrest
MOLT-4 Apoptosis and
RPMI-8402 accumulation
SUP-B15 of polyploidy
CCRF-CEM
AURKB In vitro AML HL-60 NR Barasertib Cytarabine Increase in cytotoxicity 66
HL-60/ara-C20 (AZD1152- Induced polyploidy
U937 HQPA) Apoptosis
Inhibited AURKB
auto-phosphorylation
AURKA/B/C In vitro and ALL UCSF02 BRC–ABL1 Danusertib Lonafarnib, Reduced viability 67
in vivo TXL2 BRC– (PHA- Vincristine Induced apoptosis
BLQ1 ABL1T315I 739358) and Dasatinib and polyploidy
Pt2 TP53 G2/M cell
US6 cycle arrest
US7 Reduced BCR–ABL
US7R and AURKB
phosphorylation in vivo
AURKB In vitro and NHL TOLEDO TP53 AT9283 Docetaxel Inhibited cell proliferation 68
in vivo (DLBCL, RL p16 and AURKB
MCL, T-FL, MCL phosphorylation
Burkitt’s Granta-519 Increased polyploid cells
lymphoma) Granta-4 Apoptosis
SUDHL-4 Inhibited tumor growth
SUDHL-6
Raji
AURKA In vitro with AML stem NB4 NR C1368 Cytarabine Inhibition of cell 69
validation in cells KG1 proliferation
patient samples Apoptosis
Reduction of AURKA
phosphorylation
and expression
AURKA In vitro NHL Granta-519 TP53 MK-8745 NR G2/M cell-cycle arrest 70
(MCL, Jeko1 Inhibited phosphorylation
Burkitt’s JVM2 of AURKA
Lymphoma, Z138C Apoptosis
and Akata
NK-cells DHL16
lymphoma) SUDHL-16
KAI3
SNK6
ALL: Acute lymphoblastic leukemia; AML: acute myeloid leukemia; ARA-C: cytarabine; AURKA: aurora kinase a; AURKB: aurora kinase b; CLL:
chronic lymphoblastic leukemia; CML: chronic myeloid leukemia; DHL: double-hit lymphoma; DLBCL: diffuse large B-cell lymphoma; IR: imatinib
resistant; MCL: mantle-cell lymphoma; NHL: non-Hodgkin lymphoma; NR: not reported; NK: natural killer; NILR: nilotinib resistant; T-FL:
transformed follicular lymphoma.
117CANCER DIAGNOSIS & PROGNOSIS 1: 111-126 (2021) more frequent than Hodgkin’s disease and corresponds to 123), a selective inhibitor of AURKA that is also under around 90% of head and neck malignancies (105, 106). Of investigation for relevance in the treatment of non- NHL subtypes, follicular and diffuse large B-cell lymphomas hematological malignancies (125). While it was most are the most frequently diagnosed, corresponding to about effective when treating patients with AML, this finding may 20% and 30%, respectively. Other subtypes account for also be correlated to its use as a synergistic compound fewer than 10% of the cases (107). alongside conventional induction chemotherapy (113, 114). Studies have shown that AURKA is overexpressed in A study cohort by Goldberg et al. demonstrated alisertib to several NHL subtypes when compared to normal tissues and be potentially clinically effective for patients with AML, B-cells, Chowdhury et al. evaluated the protein expression while having no efficacy when treating those with of AURKA and the potential of AURKA inhibitor, MK-8745, myelodysplastic syndrome, hinting towards a better in NHL derived from Mantle cell, Burkitt’s, and natural understanding of the drug mechanism of action and killer-cell lymphomas. Most of the cell lines analyzed biological pathway (122). presented enhanced AURKA expression but the results While most investigated drugs were AURKA-selective showed that treatment with pan-AKI VE-465 and taxol, inhibitors or pan-AKIs, AURKB was selectively targeted by when used alone, had higher toxicity than the selective the use of barasertib in two studies (119, 124). Although its inhibitor. However, the antitumoral effect of AURKA efficacy was demonstrated in the treatment of patients with inhibitor was correlated with the expression of AURKA diffuse large B-cell lymphoma, the low progression-free activator TPX2 (70). survival of 60 days attested to by Collins et al. discredits its Moreover, the pan-AKI AT9283 exhibited highly cytotoxic use as a monotherapy for this disease (119). When treating effects in NHL cells and, when used in combination with patients with AML, Kantarjian et al. demonstrated docetaxel, enhanced apoptosis, as well as survival rates and barasertib to achieve better complete response rates as a reduced tumor volume in the mouse mantle cell lymphoma monotherapy than low-dose cytosine arabinoside, an agent xenograft model (68). The synergistic effect of AURK previously demonstrated to be clinically beneficial in inhibition was observed with other antitumoral agents that clinical trials (124, 126). target the cell cycle and microtubular constituents. The Other inhibitors that were reported in only one study disruption in replication machinery leads to selective cancer include AMG 900, AT9283, ENMD-2076 and MK-0457. cell death, enhancing the antitumoral potential of AKI in These drugs had only modest to no efficacy when utilized as oncohematological treatment (108, 109). single agents and in low, tolerable doses, although ENMD- Kong et al. evaluated the synergism between the inhibitors 2076 monotherapy still achieved a 25% overall response rate of AURKA, alisertib, and BCL2 apoptosis regulator (BCL2) when treating patients with AML and CML, and should be ABT-199, in cell lines of the NHL subtype double-hit taken into account when considering possible synergistic lymphoma. Interestingly, the BCL2 inhibitor showed better interactions (115-117, 121). results in vitro than AURKA inhibitor but the ABT-199 plus Overall, the usage of AKIs did not cause unexpected or alisertib treatment synergistically inhibited viability in unmanageable adverse effects in patients and the main ones double-hit lymphoma cells (62). This subtype of NHL is were related to blood or gastrointestinal disorders (115, 117, characterized by MYC proto-oncogene (MYC) and BCL2 119-121, 123), which is in accordance with the expected translocation, MYC and AURKA are regulated by each other effects of aurora inhibition in non-malignant rapidly dividing in a feedback pathway and exert a strong role in the cell cells due to mitosis impairment (127, 128). cycle and replicative process (110). BCL2 regulates the apoptotic process and has a function in survival and Conclusion chemoresistance in hematological malignancies (111, 112). Thus, dual inhibitory therapy focusing on AURKA and The interest in understanding the involvement of aurora in BCL2 may be an interesting option for treatment in patients biological pathways in non-malignant as well as in malignant with double-hit lymphoma with these specific mutations. cells has only grown over the years. While there is still much Table II presents clinical trials from the past 10 years to be elucidated, it is clear that these kinases and their utilizing AKIs as a therapeutic option for patients afflicted by upstream and downstream regulators play a key role in leukemia and other hematological disorders. The most common mitosis and oncogenesis, motivating their investigation as studied disorder was AML, appearing in seven out of 12 potential targets for oncological treatments. Even though the studies (113-117, 122, 124), while the most targeted kinase was clinical trials using AKIs as a monotherapy for hematological AURKA, appearing in 10 of 12 studies (113-118, 120-123). disorders have not shown great results, the manageable AURKC was not a main target in any of the selected studies. toxicity and potentially synergistic effects still render them In all clinical trials presented, the most prevalent a focus of interest for future investigations in combinatorial therapeutic option was alisertib (113, 114, 118, 120, 122, clinical trials. 118
Machado et al: Aurora Kinases in Hematological Malignancies (Review)
Table II. Clinical trials utilizing aurora-kinase inhibitors as a monotherapy or in combination with synergetic treatments in the past 10 years.
Kinase assessed Study Patients Leukemia Aurora Synergistic Prognostic Reference
phase enrolled subtype inhibitor treatment significance
AURKA II 39 (64% Male) AML Alisertib Cytarabine and Remission was 113
Median age=67 years (MLN8237) idarubicin achieved in 64%
AURKA I 22 (68% Male) AML Alisertib Cytarabine and Remission was 114
Median age=62.7 years (MLN8237) idarubicin achieved in 86%
AURKA/B I 35 (66% Male) AML AMG 900 NR Complete response 115
Median age=69 years with incomplete count
recovery was
achieved in 9%
AURKA/B I/II 7 (71% Male) AML AT9283 NR None of the patients 116
Median age=3 years ALL achieved a partial or
complete remission
AURKA I 27 (74% Male) AML ENMD-2076 NR Overall response 117
Median age=69 years CML rate was 25%
AURKA I 26 (61.5% Male) MM Alisertib Bortezomib Overall response 118
Median age=64.5 years (MLN8237) rate was 26.9%
AURKB II 15 (53% Male) DLBCL Barasertib NR Overall response 119
Median age=65 years (AZD1152-HQPA) rate was 20%
AURKA II 48 (73% Male) Non-Hodgkin Alisertib NR Overall response 120
Median age=67.5 years lymphoma (MLN8237) rate was 27%
AURKA/B II 52 (65% Male) CML MK-0457 NR Only 3.8% had complete 121
Median age=52 years ALL cytogenetic and
hematological response
AURKA II 57 (56% Male) AML Alisertib NR Overall response 122
Median age=72 years MDS (MLN8237) rate was 13%
AURKA I 58 (47% Male) MM Alisertib NR Overall response 123
Median age=61 years NHL (MLN8237) rate was 27%
CLL
AURKB II 77 (58.4% Male) AML Barasertib NR Complete response 124
Median age=76 years (AZD1152-HQPA) rate of 35.4%
ALL: Acute lymphoid leukemia; AML: acute myeloid leukemia; AURKA: aurora kinase A; AURKB: aurora kinase B; CML: chronic myeloid
leukemia; DLBCL: diffuse large B-cell lymphoma; MDS: myelodysplastic syndrome; MM: multiple myeloma; NHL: non-Hodgkin’s lymphoma;
NR: not reported.
Conflicts of Interest Moraes-Filho MO, Moraes MEA, Montenegro RC and Moreira-
Nunes CA wrote the article. All Authors read and approved the final
The Authors declare no conflicts of interest regarding this study. article.
Authors’ Contributions Acknowledgements
Machado CB, da Silva EL and Moreira-Nunes CA, performed the This study was supported by Brazilian funding agencies National
study design; Machado CB and Nogueira BMD, prepared the Counsel of Technological and Scientific Development (CNPq; to
figures; Machado CB, da Silva EL, Nogueira BMD, da Silva JBS, ELS, RCM, MEAM, MOMF and CAMN).
119CANCER DIAGNOSIS & PROGNOSIS 1: 111-126 (2021)
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