Combination of an aurora kinase inhibitor and the ABL tyrosine kinase inhibitor asciminib against ABL inhibitor-resistant CML cells.
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
/ drug therapy
Drug Resistance, Neoplasm
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Aurora Kinase A
/ antagonists & inhibitors
Cell Line, Tumor
Fusion Proteins, bcr-abl
/ antagonists & inhibitors
Aurora Kinase B
/ antagonists & inhibitors
Apoptosis
/ drug effects
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Cell Proliferation
/ drug effects
Tyrosine Kinase Inhibitors
Niacinamide
/ analogs & derivatives
Pyrazoles
ABL tyrosine kinase inhibitor resistance
Asciminib
Aurora kinase inhibitor
BCR::ABL1
Chronic myeloid leukemia
Journal
Medical oncology (Northwood, London, England)
ISSN: 1559-131X
Titre abrégé: Med Oncol
Pays: United States
ID NLM: 9435512
Informations de publication
Date de publication:
07 May 2024
07 May 2024
Historique:
received:
03
03
2024
accepted:
24
04
2024
medline:
8
5
2024
pubmed:
8
5
2024
entrez:
7
5
2024
Statut:
epublish
Résumé
The development of BCR::ABL1-targeting tyrosine kinase inhibitors (TKIs) has improved the prognosis of patients with chronic myeloid leukemia (CML). However, resistance to ABL TKIs can develop in CML patients due to BCR::ABL1 point mutations and CML leukemia stem cell (LSC). Aurora kinases are essential kinases for cell division and regulate mitosis, especially the process of chromosomal segregation. Aurora kinase members also promote cancer cell survival and proliferation. This study analyzed whether aurora kinases were regulated in the progression of CML. It also evaluated the efficacy of the ABL TKI asciminib and the aurora kinase inhibitor LY3295668. The expressions of AURKA and AURKB were higher in the CML cells compared with normal cells using a public database (GSE100026). Asciminib or LY3295668 alone inhibited CML cells after 72 h, and cellular cytotoxicity was increased. The combined use of Asciminib and LY3295668 increased superior efficacy compared with either drug alone. Colony formation was reduced by cotreatment with asciminib and LY3295668. In the cell-cycle analyses, LY3295668 induced G2/M arrest. Cell populations in the sub-G1 phase were observed when cotreating with asciminib and LY3295668. The combination treatment also changed the mitochondrial membrane potential. In addition, AURKA shRNA transfectant cells had increased asciminib sensitivity. Combining asciminib and aurora kinase inhibition enhanced the efficacy and is proposed as a new therapeutic option for patients with CML. These findings have clinical implications for a potential novel therapeutic strategy for CML patients.
Identifiants
pubmed: 38714583
doi: 10.1007/s12032-024-02394-6
pii: 10.1007/s12032-024-02394-6
doi:
Substances chimiques
Protein Kinase Inhibitors
0
asciminib
0
Aurora Kinase A
EC 2.7.11.1
Fusion Proteins, bcr-abl
EC 2.7.10.2
AURKA protein, human
EC 2.7.11.1
Aurora Kinase B
EC 2.7.11.1
AURKB protein, human
EC 2.7.11.1
Tyrosine Kinase Inhibitors
0
Niacinamide
25X51I8RD4
Pyrazoles
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
142Subventions
Organisme : The Japanese Ministry of Education, Culture, Sports, Science, and Technology
ID : 20K07644
Informations de copyright
© 2024. The Author(s).
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