Hyper-activation of Aurora kinase a-polo-like kinase 1-FOXM1 axis promotes chronic myeloid leukemia resistance to tyrosine kinase inhibitors

Abstract

Background Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the constitutive tyrosine kinase (TK) activity of the BCR-ABL1 fusion protein. Accordingly, TK inhibitors have drastically changed the disease prognosis. However, persistence of the transformed hematopoiesis even in patients who achieved a complete response to TK inhibitors and the disease relapse upon therapy discontinuation represent a major obstacle to CML cure. Methods Thiostrepton, Danusertib and Volasertib were used to investigate the effects of FOXM1, AKA and Plk1 inhibition in K562-S and K562-R cells. Apoptotic cell death was quantified by annexin V/propidium iodide staining and flow cytometry. Quantitative reverse transcription (RT)-PCR was used to assess BCR-ABL1, FOXM1, PLK1 and AURKA expression. Protein expression and activation was assessed by Western Blotting (WB). Clonogenic assay were performed to confirm K562-R resistance to Imatinib and to evaluate cells sensitivity to the different drugs. Results Here we proved that BCR-ABL1 TK-dependent hyper-activation of Aurora kinase A (AURKA)-Polo-like kinase 1 (PLK1)-FOXM1 axis is associated with the outcome of Imatinib (IM) resistance in an experimental model (K562 cell line) and bone marrow hematopoietic cells. Notably, such a biomolecular trait was detected in the putative leukemic stem cell (LSC) compartment characterized by a CD34+ phenotype. Constitutive phosphorylation of FOXM1 associated with BCR-ABL1 TK lets FOXM1 binding with β-catenin enables β-catenin nuclear import and recruitment to T cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription complex, hence supporting leukemic cell proliferation and survival. Lastly, the inhibition of single components of AURKA-PLK1-FOXM1 axis in response to specific drugs raises the expression of growth factor/DNA damage-inducible gene a (GADD45a), a strong inhibitor of AURKA and, as so, a critical component whose induction may mediate the eradication of leukemic clone. Conclusions Our conclusion is that AURKA, PLK1 and FOXM1 inhibition may be considered as a promising therapeutic approach to cure CML. Electronic supplementary material The online version of this article (10.1186/s13046-019-1197-9) contains supplementary material, which is available to authorized users.

Ponatinib treatment in chronic myeloid leukemia cell lines targets aurora kinase A/FOXM1 axis

“…GADD45a is a target of AKA/FOXM1 axis, acting as a repressor of cell proliferation in response to TKIs. 3 Here, we confirmed GADD45a induction in response to imatinib in the K562-S cell line, its down-regulation in K562-IR cells and its re-induction in response to ponatinib in the same cell context ( Figure 1H). Conversely, K562-PR cells exhibited a significantly higher GADD45a expression level compared to K562-S and K562-PR cells, not affected by the exposure to ponatinib ( Figure 1H).…”

“…We then investigated the stress sensor growth arrest/DNA damage‐inducible (GADD) 45 gene, which physically associates with AKA and strongly inhibits its activity. GADD45a is a target of AKA/FOXM1 axis, acting as a repressor of cell proliferation in response to TKIs . Here, we confirmed GADD45a induction in response to imatinib in the K562‐S cell line, its down‐regulation in K562‐IR cells and its re‐induction in response to ponatinib in the same cell context (Figure H).…”

“…However, BCR‐ABL1‐independent TKI resistance has also been reported to occur in a significant fraction of CML patients. In a recent study, we have proven that the over‐expression and hyper‐activation of the Aurora kinase A (AKA)‐FOXM1 axis contribute to evade death in IM‐resistant BCR‐ABL1+ cells . Results presented here suggest that resistance to ponatinib may equally be BCR‐ABL1‐independent, but that does not involve the AKA‐FOXM1 axis.…”

“…In a recent study, we showed that imatinib resistance may be associated with the over-expression and hyper-activation of the AKA/FOXM1 axis and that both AKA and FOXM1 inhibitors have a significant effect on cell survival. 3 Here, we investigated whether ponatinib resistance exhibits a similar protein expression profile. To perform our experiments, we maintained K562-IR and K562-PR cell lines in permanent imatinib and ponatinib selection (10μM and 50nM, respectively).…”

<p>Identification of Aurora Kinase A as a Biomarker for Prognosis in Obesity Patients with Early Breast Cancer</p>

“…29,30 Studies of antiestrogens resistance breast cancer cell culture models by mimicking ER disclosed that Aurora A was increased and mediated cell proliferation and cell cycle in both antiestrogen and aromatase inhibitor resistant breast cancer cells. [31][32][33] Comprehensive analyses with a library of 195 kinase inhibitors identified Aurora A inhibitor JNJ-7706621 as a preferential inhibitor of endocrine therapy resistant breast cancer cell lines. 34 Resensitivity to tamoxifen treatment was recovered with Aurora A siRNA or Aurora A inhibitor, indicating a vital role for Aurora A in endocrine therapy resistance.…”