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Tytuł pozycji:

Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression.

Tytuł:
Aurora A kinase inhibition compromises its antitumor efficacy by elevating PD-L1 expression.
Autorzy:
Wang X; Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Huang J; Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; China University of Chinese Academy of Sciences, Beijing, China.
Liu F; Department of General Surgery and.
Yu Q; Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Wang R; Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Wang J; Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Zhu Z; Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Yu J; Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
Hou J; Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China.
Shim JS; Department of Pharmaceutical Sciences and Cancer Centre, Faculty of Health Science, University of Macau, Taipa, Macau SAR, China.
Jiang W; Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Li Z; Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Zhang Y; Drug Discovery and Design Center, the Center for Chemical Biology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.; China University of Chinese Academy of Sciences, Beijing, China.
Dang Y; Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.; Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, The Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, Chongqing, China.
Źródło:
The Journal of clinical investigation [J Clin Invest] 2023 May 01; Vol. 133 (9). Date of Electronic Publication: 2023 May 01.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Publication: 1999- : Ann Arbor, MI : American Society for Clinical Investigation
Original Publication: New Haven [etc.] American Society for Clinical Investigation.
MeSH Terms:
Aurora Kinase A*/genetics
Aurora Kinase A*/metabolism
Protein Kinase Inhibitors*/pharmacology
Protein Kinase Inhibitors*/therapeutic use
Animals ; Mice ; B7-H1 Antigen/genetics ; Cell Line, Tumor ; Nucleotidyltransferases ; Humans
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Contributed Indexing:
Keywords: Cancer; Drug therapy; Oncology
Substance Nomenclature:
EC 2.7.11.1 (Aurora Kinase A)
0 (B7-H1 Antigen)
0 (CD274 protein, human)
EC 2.7.7.- (Nucleotidyltransferases)
0 (Protein Kinase Inhibitors)
Entry Date(s):
Date Created: 20230317 Date Completed: 20230508 Latest Revision: 20230520
Update Code:
20240105
PubMed Central ID:
PMC10145933
DOI:
10.1172/JCI161929
PMID:
36928177
Czasopismo naukowe
Aurora A plays a critical role in G2/M transition and mitosis, making it an attractive target for cancer treatment. Aurora A inhibitors showed remarkable antitumor effects in preclinical studies, but unsatisfactory outcomes in clinical trials have greatly limited their development. In this study, the Aurora A inhibitor alisertib upregulated programmed death ligand 1 (PD-L1) expression in a panel of tumor cells both in vitro and in vivo. Upregulation of the checkpoint protein PD-L1 reduced antitumor immunity in immune-competent mice, paradoxically inhibiting the antitumor effects of alisertib. Mechanistically, Aurora A directly bound to and phosphorylated cyclic GMP-AMP synthase (cGAS), suppressing PD-L1 expression in tumor cells. Aurora A inhibition by alisertib activated the cGAS/stimulator of IFN genes (STING)/NF-κB pathway and promoted PD-L1 expression. Combining alisertib with anti-PD-L1 antibody improved antitumor immunity and enhanced the antitumor effects of alisertib in immune-competent mice. Our results, which reveal the immunomodulatory functions of Aurora A inhibitors and provide a plausible explanation for the poor clinical outcomes with their use, offer a potential approach to improve the antitumor efficacy of these inhibitors.

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