The ALK inhibitor AZD3463 effectively inhibits growth of sorafenib-resistant acute myeloid leukemia

Moharram, Sausan A.; Shah, Kinjal; Khanum, Fatima; Rönnstrand, Lars

doi:10.1038/s41408-018-0169-1

Cited by 5 publications

(3 citation statements)

References 12 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…4a) raised the possibility that the resistant cells carry an oncogenic internal tandem duplication (ITD) mutation in FLT3, which typically gives this pattern of expression. 15,16 This is also supported by the fact that resistant RS4;11 cells showed constitutive tyrosine phosphorylation of FLT3 as well as constitutive STAT5 phosphorylation (Fig. 4b) and that the second-generation FLT3 inhibitor AC220 could block tyrosine phosphorylation of both FLT3 and STAT5 (Fig.…”

Section: Resultsmentioning

confidence: 52%

Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation

et al. 2019

Self Cite

View full text Add to dashboard Cite

The response of childhood acute lymphoblastic leukemia (ALL) to dexamethasone predicts the long-term remission outcome. To explore the mechanisms of dexamethasone resistance in B cell ALL (B-ALL), we generated dexamethasone-resistant clones by prolonged treatment with dexamethasone. Using RNA-sequencing and high-throughput screening, we found that dexamethasone-resistant cells are dependent on receptor tyrosine kinases. Further analysis with phosphokinase arrays showed that the type III receptor tyrosine kinase FLT3 is constitutively active in resistant cells. Targeted next-generation and Sanger sequencing identified an internal tandem duplication mutation and a point mutation (R845G) in FLT3 in dexamethasone-resistant cells, which were not present in the corresponding sensitive clones. Finally, we showed that resistant cells displayed sensitivity to second-generation FLT3 inhibitors both in vitro and in vivo. Collectively, our data suggest that long-term dexamethasone treatment selects cells with a distinct genetic background, in this case oncogenic FLT3, and therefore therapies targeting FLT3 might be useful for the treatment of relapsed B-ALL patients.

show abstract

Section: Resultsmentioning

confidence: 52%

Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…To measure global kinase activity, we used peptide substrate-based kinase profiling. Pamgene peptide substrate-based kinase profiling has been demonstrated to be a powerful technique for determining kinase activity 17 , 18 . SUP-B15 cells were treated with dexamethasone (1 µM) or DMSO for 6 h before lysis.…”

Section: Resultsmentioning

confidence: 99%

The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia

2021

Self Cite

View full text Add to dashboard Cite

Glucocorticoids, such as dexamethasone and prednisolone, are widely used in cancer treatment. Different hematological malignancies respond differently to this treatment which, as could be expected, correlates with treatment outcome. In this study, we have used a glucocorticoid-induced gene signature to develop a deep learning model that can predict dexamethasone sensitivity. By combining gene expression data from cell lines and patients with acute lymphoblastic leukemia, we observed that the model is useful for the classification of patients. Predicted samples have been used to detect deregulated pathways that lead to dexamethasone resistance. Gene set enrichment analysis, peptide substrate-based kinase profiling assay, and western blot analysis identified Aurora kinase, S6K, p38, and β-catenin as key signaling proteins involved in dexamethasone resistance. Deep learning-enabled drug synergy prediction followed by in vitro drug synergy analysis identified kinase inhibitors against Aurora kinase, JAK, S6K, and mTOR that displayed synergy with dexamethasone. Combining pathway enrichment, kinase regulation, and kinase inhibition data, we propose that Aurora kinase or its several direct or indirect downstream kinase effectors such as mTOR, S6K, p38, and JAK may be involved in β-catenin stabilization through phosphorylation-dependent inactivation of GSK-3β. Collectively, our data suggest that activation of the Aurora kinase/β-catenin axis during dexamethasone treatment may contribute to cell survival signaling which is possibly maintained in patients who are resistant to dexamethasone.

show abstract

“…Thus, although DZNep can suppress breast cancer, it simultaneously increases osteolysis. To prevent osteoclastic resorption, we introduced another anti-cancer agent, AZD3463, that promisingly induced apoptosis by inhibiting the PI3K-Akt pathway in breast cancer (Hu et al, 2020;Ozates et al, 2021), neuroblastoma (Wang et al, 2016), glioblastoma (Asik et al, 2020;Goker Bagca et al, 2020), acute myeloid leukemia (Moharram et al, 2019), and Ewing sarcoma (Sampson et al, 2015). Akt activation is associated with worse outcomes in endocrine-related breast cancer (Pérez-Tenorio et al, 2002), so targeting this signaling pathway is a classic research focus (Guerrero-Zotano et al, 2016;Costa et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Combination of AZD3463 and DZNep Prevents Bone Metastasis of Breast Cancer by Suppressing Akt Signaling

Cao

Rong

et al. 2021

Front. Pharmacol.

View full text Add to dashboard Cite

Osteolysis resulting from osteoclast overactivation is one of the severe complications of breast cancer metastasis to the bone. Previous studies reported that the anti-cancer agent DZNep induces cancer cell apoptosis by activating Akt signaling. However, the effect of DZNep on breast cancer bone metastasis is unknown. We previously found that DZNep enhances osteoclast differentiation by activating Akt. Therefore, we explored the use of the anti-cancer agent AZD3463 (an Akt inhibitor) along with DZNep, as AZD3463 can act as an anti-cancer agent and can also potentially ameliorate bone erosion. We evaluated osteoclast and breast cancer cell phenotypes and Akt signaling in vitro by treating cells with DZNep and AZD3463. Furthermore, we developed a breast cancer bone metastasis animal model in mouse tibiae to further determine their combined effects in vivo. Treatment of osteoclast precursor cells with DZNep alone increased osteoclast differentiation, bone resorption, and expression of osteoclast-specific genes. These effects were ameliorated by AZD3463. The combination of DZNep and AZD3463 inhibited breast cancer cell proliferation, colony formation, migration, and invasion. Finally, intraperitoneal injection of DZNep and AZD3463 ameliorated tumor progression and protected against bone loss. In summary, DZNep combined with AZD3463 prevented skeletal complications and inhibited breast cancer progression by suppressing Akt signaling.

show abstract

The ALK inhibitor AZD3463 effectively inhibits growth of sorafenib-resistant acute myeloid leukemia

Cited by 5 publications

References 12 publications

Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation

Glucocorticoid-resistant B cell acute lymphoblastic leukemia displays receptor tyrosine kinase activation

The Aurora kinase/β-catenin axis contributes to dexamethasone resistance in leukemia

Combination of AZD3463 and DZNep Prevents Bone Metastasis of Breast Cancer by Suppressing Akt Signaling

Contact Info

Product

Resources

About