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A novel compound against oncogenic Aurora kinase A overcomes imatinib resistance in chronic myeloid leukemia cells
Zi-Jie Long1, Le-Xun Wang1, Fei-Meng Zheng2
1Department of Hematology, The Third Affiliated Hospital, Sun Yat-sen University, Sun Yat-sen Institute of Hematology, Guangzhou 510630, P.R. China.
Abstract:
Drug resistance still represents a major obstacle to successful chronic myeloid leukemia (CML) treatment and novel compounds or strategies to override this challenging problem are urgently required. Here, we evaluated a novel compound AKI603 against oncogenic Aurora kinase A (Aur-A) in imatinib-resistant CML cells. We found that Aur-A was highly activated in imatinib-resistant KBM5-T315I cells. AKI603 significantly inhibited the phosphorylation of Aur-A kinase at Thr288, while had little inhibitory effect on BCR-ABL kinase in both KBM5 and KBM5-T315I cells. AKI603 inhibited cell viability, and induced cell cycle arrest with polyploidy accumulation in KBM5 and KBM5-T315I cells. Moreover, inhibition of Aur-A kinase by AKI603 suppressed colony formation capacity without promoting obvious apoptosis. Importantly, AKI603 promoted cell differentiation in both CML cell types. Thus, our study suggested the potential clinical use of small molecule Aurora kinase inhibitor AKI603 to overcome imatinib resistance in CML treatment.
Insights
A novel compound, AKI603, effectively targets Aurora kinase A in imatinib-resistant chronic myeloid leukemia (CML) cells. This compound inhibits cancer cell growth and promotes differentiation, offering a potential strategy to overcome drug resistance in CML treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Drug resistance remains a significant challenge in chronic myeloid leukemia (CML) treatment.
- Novel therapeutic strategies are needed to overcome resistance to existing therapies like imatinib.
- Aurora kinase A (Aur-A) is implicated in cancer cell proliferation and survival.
Purpose of the Study:
- To evaluate the efficacy of a novel compound, AKI603, as an inhibitor of Aurora kinase A (Aur-A).
- To assess AKI603's activity against imatinib-resistant chronic myeloid leukemia (CML) cells.
- To investigate AKI603's mechanism of action in CML cells.
Main Methods:
- In vitro evaluation of AKI603 in imatinib-resistant KBM5-T315I and KBM5 CML cell lines.
- Assessment of Aur-A kinase phosphorylation inhibition at Thr288.
- Analysis of cell viability, cell cycle progression, polyploidy, colony formation, apoptosis, and cell differentiation.
- Evaluation of AKI603's effect on BCR-ABL kinase activity.
Main Results:
- Aur-A was highly activated in imatinib-resistant KBM5-T315I cells.
- AKI603 significantly inhibited Aur-A phosphorylation at Thr288 but had minimal effect on BCR-ABL kinase.
- AKI603 reduced cell viability, induced cell cycle arrest with polyploidy, and suppressed colony formation.
- AKI603 promoted cell differentiation in both CML cell types without significant apoptosis induction.
Conclusions:
- Small molecule Aurora kinase inhibitor AKI603 demonstrates potent activity against imatinib-resistant CML cells.
- AKI603's mechanism involves Aur-A inhibition, leading to cell cycle arrest, polyploidy, and differentiation.
- AKI603 shows potential as a therapeutic agent to overcome imatinib resistance in CML treatment.
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