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Short Review | DOI: https://doi.org/10.31579/2640-1053/051
1 Department of Internal Medicine, University of California Davis, USA
*Corresponding Author: Edward J. Kim, UC Davis Comprehensive Cancer Center, Sacramento, CA 95817 USA.
Citation: Jasmine C. Huynh, Justin A. Chen, Mili Arora, May Cho, Edward J. Kim. Strategic Combinations of Aurora Kinase an Inhibiton with Targeted Drugs for Synergistic Anti-Tumor Effect, J. Cancer Research and Celllular Therapeutics . Doi:10.31579/2640-1053/051
Copyright: © 2019 Edward J. Kim, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are credited.
Received: 25 May 2019 | Accepted: 06 June 2019 | Published: 07 June 2019
Keywords: aurora kinase A; mitotic inhibitor; cell cycle; tumorigenesis
Inhibition of mitosis is an established therapeutic approach in the treatment of cancer. However, existing drugs that use this mechanism including taxanes cause off-target effects leading to dose-limiting toxicity such as sensory neuropathy. Development of inhibitors of mitosis-specific targets has created the next generation of mitosis inhibitors with the goal of achieving similar anti-tumor efficacy but with less toxicity. Aurora Kinase A is one example of a mitosis-specific target for which multiple drugs have been developed as anti-cancer therapy. Although early preclinical studies have showed on-target effects, clinical development has been slowed by minimal efficacy as monotherapy. However, strategic combinations of Aurora Kinase A inhibition with various targeted drugs has shown promise and led to renewed interest in the potential of inhibiting this mitosis-specific target.
The Aurora Kinase family is comprised of three members; Aurora Kinase A (AKA), Aurora Kinase B (AKB) and Aurora Kinase C (AKC). Aurora Kinases are serine/threonine kinases that regulate chromosomal segregation during mitosis and meiosis. AKA and AKB are expressed in most cell types whereas AKC is only expressed in the testis. AKA controls premetaphase events, AKB is crucial for precise chromosome segregation and cytokinesis, and AKC and controls spermatogenesis [1-3]. Though all members of the Aurora Kinase family have oncogenic properties, AKA was the first family member to be identified as one of the main kinases that regulates cell proliferation and for this reason, is an attractive drug target1. This review focuses on AKA as a potential target for next-generation mitotic inhibition, especially in combination with other targeted agents.
AKA plays a crucial role in centrosome maturation, mitotic entry, G2/M transition, spindle assembly and cytokinesis [2,4,5]. In normal cells, AKA induces phosphorylation of TACC, leading to complex formation with XMAP215 to promote centrosomal microtubule stabilization [2,6,7]. Prior to M phase, AKA couples with Bora to induce phosphorylation and activation of PLK. Activated PLK1 then activates CDK1/cyclin B via degradation of Wee1, a CDK-inhibitory kinase, and activation of CDK-promoting phosphatase CDC25C. Simultaneously, AKA activates CDC25B, another CDK-activator. This series of events further enhances the G2/M transition2. AKA additionally phosphorylates Ajuba which is a LIM protein and this interaction forms a positive feedback loop to initiate mitosis. There is an additional positive feedback loop between AKA and TPX2, and deficiencies in either component leads to defective spindle formation2.
Role of AKA in tumorigenesis
AKA has several roles in tumorigenesis and has been associated with multiple cancers, including breast cancer, gliomas, lung cancer, head and neck carcinoma, gastric cancer, esophageal cancer, and hematologic malignancies. In general, cancer cells with AKA overexpression have amplified centrosomes and multipolar spindles, genomic instability due to failure to resolve cytokinesis, and aberrant activation of pro-oncogenic signaling pathways, such as the nuclear factor kB and B-catenin/WNT pathway [4,8,9]. AKA’s specific role in tumorigenesis has been investigated in multiple tumor types. AKA has been shown to prevent N-myc degradation in neuroblastoma10, promote epithelial-to-mesenchymal transition (EMT) in breast cancer cells11, and promote growth of KRAS-mutant lung and GI tumor cells potentially through phosphorylation of RPS6KB1 [8,12].
Targeting AKA for cancer therapy
Given AKA’s role in tumorigenesis, inhibition of AKA has been an attractive strategy based on its potential to provide a novel effective way to suppress cancer progression. Multiple AKA inhibitors have been developed, including MLN8237 (alisertib), MK5108 (VX-689), and MLN80541. Alisertib has progressed the furthest in clinical development among the AKA inhibitors and has been tested in multiple Phase I-II trials, with some Phase III trials emerging [13-18]. However, AKA inhibitors as monotherapy have consistently disappointed demonstrating minimal clinically meaningful efficacy. A phase III study of single-agent alisertib in relapsed/refractory peripheral T-cell lymphoma showed no improvement of progression-free survival or response rate compared to investigator’s choice, leading to early study termination18.
Combining inhibition of AKA with targeted drugs
This overall poor response of cancer cells to AKA inhibition alone has led to investigation of combination strategies anchored on AKA inhibition.
Wee1 inhibitor
In TP53-mutant HNSCC cells, the addition of adavosertib, a Wee1 inhibitor, to alisertib resulted in mitotic catastrophe-mediated cell death through highly abnormal mitoses with unaligned, dispersed chromosomes, disorganized multipolar spindles, and distorted and ballooned cellular morphology4. Cells treated with combination therapy also showed increased levels of cleaved-PARP, suggesting induction of apoptosis. These findings were confirmed in in vivo models where combination therapy dramatically decreased tumor growth and prolonged survival of mice compared to vehicle or single-agent therapy. Additionally, murine weight remained stable suggesting the combination was minimally toxic. Mechanistically, Wee1 is an inhibitor of CDK1; its addition promotes cell-cycle progression, mitotic entry, and transition through the G2/M-checkpoint in the presence of defective spindle assembly and failed centrosome maturation induced by AKA inhibition, thus resulting in mitotic catastrophe.
MEK inhibitor
MEK is part of the MAPK signaling pathway and affects cellular response to DNA damage [19,20]. This has led to the hypothesis that combining MEK inhibition with AKA inhibition may result in more robust cell death. MEK inhibition disrupts DNA repair and cell cycle progression in G1, thus addition of MEK inhibitors promotes genomic instability induced by AKA inhibition and facilitates sustained cell cycle arrest [19,21,22]. Furthermore, MEK inhibition can induce degradation of c-Myc which upregulates expression of AKA in hepatocellular carcinoma and B-cell lymphomas [19,23,24]. In BRAF-mutant melanoma cell lines, combination trametinib (MEK inhibitor) and MLN8054 had more pronounced anti-proliferative effects as compared to combination trametinib and dabrafenib, the latter of which is a now a first-line regimen in BRAF-mutated advanced melanomas[19,25]. In KRAS- and PIK3CA-mutant colorectal cancer cell models, combining alisertib with MEK inhibition led to a more robust anti-proliferative response19.
BH3 mimetic
The Bcl2 family of proteins include both pro- and anti-apoptotic members that share Bcl2 homology (BH) domains including BH3. BH3 mimetics such as ABT263 block select anti-apoptotic members of the Bcl2 family of proteins but fail to inhibit all, including MCL-126. This incomplete blockade is thought to be one potential pathway of resistance to BH3 mimetic monotherapy. MLN8237 induces mitotic arrest which leads to MCL-1 degradation, thus introducing a way to overcome this potential resistance mechanism. In four pancreatic cancer cell lines treated with monotherapy MLN8237 or ABT263, there was variable sensitivity to either single agent26. However, combination MLN8237 and ABT263 resulted in a synergistic increase of sensitivity in all four cell lines. In vivo testing of this combination on pancreatic cell xenografts and patient-derived pancreatic cancer organoids (PDO) showed greater tumor growth inhibition compared to either agent alone. Both pancreatic cancer cell lines and PDOs showed an increase in Caspase 3/7 activity, suggesting that an increase in apoptosis was responsible for the observed cell growth inhibition. Combining AKA inhibition with Bcl2 inhibition has also been tested in double hit lymphoma and has shown promise through arrest of cell cycle progression and promotion of apoptosis27.
EGFR inhibitor
EGFR inhibitors have become a standard treatment option for EGFR-mutated non-small cell lung cancers (NSCLC). However, inevitable development of resistance to EGFR inhibitors limits durability of response. One potential mechanism of EGFR inhibitor resistance is through an increase in expression of TPX2 which activates AKA and protects it from degradation28. Patient-derived NSCLC xenografts treated with combination rociletinib, a 3rd generation EGFR inhibitor, and MLN8237 led to stronger initial reduction in tumor growth as compared to single-agent rociletinib, which only partially abrogated tumor growth and led to rapid tumor progression. Similarly, the combination of osimertinib, another 3rd generation EGFR inhibitor, and MLN8237 resulted in decreased tumor growth in nine out of ten tested xenografts28. Combination treatment caused a decrease in ERK and NF-
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