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Review
. 2023 Jul;13(7):2826-2843.
doi: 10.1016/j.apsb.2023.03.013. Epub 2023 Mar 15.

Emerging roles of Aurora-A kinase in cancer therapy resistance

Dayong Zheng  1 , Jun Li  2 , Han Yan  1 , Gang Zhang  3 , Wei Li  1 , Edward Chu  4 , Ning Wei  4
Affiliations
Review

Emerging roles of Aurora-A kinase in cancer therapy resistance

Dayong Zheng et al. Acta Pharm Sin B. 2023 Jul.

Abstract

Aurora kinase A (Aurora-A), a serine/threonine kinase, plays a pivotal role in various cellular processes, including mitotic entry, centrosome maturation and spindle formation. Overexpression or gene-amplification/mutation of Aurora-A kinase occurs in different types of cancer, including lung cancer, colorectal cancer, and breast cancer. Alteration of Aurora-A impacts multiple cancer hallmarks, especially, immortalization, energy metabolism, immune escape and cell death resistance which are involved in cancer progression and resistance. This review highlights the most recent advances in the oncogenic roles and related multiple cancer hallmarks of Aurora-A kinase-driving cancer therapy resistance, including chemoresistance (taxanes, cisplatin, cyclophosphamide), targeted therapy resistance (osimertinib, imatinib, sorafenib, etc.), endocrine therapy resistance (tamoxifen, fulvestrant) and radioresistance. Specifically, the mechanisms of Aurora-A kinase promote acquired resistance through modulating DNA damage repair, feedback activation bypass pathways, resistance to apoptosis, necroptosis and autophagy, metastasis, and stemness. Noticeably, our review also summarizes the promising synthetic lethality strategy for Aurora-A inhibitors in RB1, ARID1A and MYC gene mutation tumors, and potential synergistic strategy for mTOR, PAK1, MDM2, MEK inhibitors or PD-L1 antibodies combined with targeting Aurora-A kinase. In addition, we discuss the design and development of the novel class of Aurora-A inhibitors in precision medicine for cancer treatment.

Keywords: Alisertib; Aurora-A; Chemoresistance; PROTAC; Radioresistance; Synthetic lethality; Targeted therapy; Therapy resistance.

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Figures

Image 1
Graphical abstract
Figure 1
Figure 1
The structure and expression of Aurora-A kinase. (A) Schematic diagram of the domain structure of Aurora kinases. The catalytic domain of Aurora-A, Aurora-B, and Aurora-C is highly conserved (all gray junction region). Autophosphorylation of Thr287/288 in the activation loop (also known as the “T-loop”) of Aurora-A is required for activation of its kinase activity. A short amino acid peptide motif called a “destruction box” (D-box) is present in the carboxy-terminal region of Aurora-A, Aurora- B, and Aurora-C. Aurora-A has the amino terminal “D-box-activating domain box (A-Box)” required for D-box functional activation. (B) The expression of Aurora-A kinase in human tissues; (C) The alteration of Aurora-A in human cancer. According to TCGA combined database, overexpression (gene amplification) and mutation of AURKA occur in various types of human cancer, including lung cancer, colorectal cancer, breast cancer, etc.
Figure 2
Figure 2
The role of Aurora-A in human cancer hallmarks and cancer acquired resistance. (A) Aurora-A plays multiple roles in regulating tumor development and progression by facilitating cell-cycle progression, activating cell survival and anti-apoptosis or necroptosis signaling, inducing genomic instability, epithelial–mesenchymal transition (EMT) and cancer stem cells (CSCs). In recent studies, some novel cancer hallmarks have been found to regulate tumor progression associated with Aurora-A kinase; (B) Mechanisms of Aurora-A-mediated cancer acquired resistance. Aurora-A kinase on producing the resistance to radiotherapy, chemotherapy and targeted therapy via modulating DNA damage repair, feedback activation bypass pathway, apoptosis, metastasis, stemness and autophagy.
Figure 3
Figure 3
Synthetic lethality and pharmacological combination strategy for targeting Aurora-A. (A) Synthetic lethality strategy for targeting Aurora-A. Aurora-A inhibitors have synthetic lethality in RB1, ARID1A and MYC gene mutation tumors, which also provides thoughts for the Aurora-A inhibitors towards individual therapy; (B) Combinational strategy for targeting Aurora-A. Aurora-A inhibitors have been demonstrated to have synergistic effects in combination with other therapeutics agents, including mTOR inhibitor, PAK1 inhibitor, MEK inhibitor, MDM2 inhibitor, PD-L1 antibody and microtubule inhibitor.
Figure 4
Figure 4
Drug design strategies for targeting Aurora-A. (A) Schematic diagram of several targeted Aurora-A approaches. LNA, locked nucleic acid; UTR, untranslated region. (B) PROTACs contain three ethylene glycol molecules linked by amides of ATP-competitive inhibitor alisertib (blue region) and thalidomide (gray region). (C) The chemical structure of allosteric inhibitor CD532. The blue region represents chemical structures of allosteric conformational destruction (CD) compound diaminopyrimidine scaffold. (D) Covalent modification of Cys290 in Aurora-A by the thiol group of the pantetheine tail of CoA.
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