Unknown

Dataset Information

0

Overcoming CML acquired resistance by specific inhibition of Aurora A kinase in the KCL-22 cell model.


ABSTRACT: Serine/threonine kinase Aurora A is essential for regulating mammalian cell division and is overexpressed in many types of human cancer. However, the role of Aurora A in chemoresistance of chronic myelogenous leukemia (CML) is not well understood. Using the KCL-22 cell culture model we have recently developed for studying mechanisms of CML acquired resistance, we found that Aurora A expression was partially reduced in these cells upon treatment with the tyrosine kinase inhibitor imatinib, which accompanied the acquisition of BCR-ABL mutation for imatinib resistance. Gene knockdown of BCR-ABL also reduced Aurora A expression, and conversely, Aurora A expression increased in hematopoietic progenitor cells after BCR-ABL expression. Inhibition of Aurora A induced apoptosis of CML cells with or without T315I BCR-ABL mutation and suppressed CML cell growth. Inhibition of Aurora A by gene knockdown or a highly specific small molecule inhibitor sensitized CML cells to imatinib treatment and effectively blocked acquisition of BCR-ABL mutations and KCL-22 cell relapse on imatinib, nilotinib or dasatinib. Our results show that Aurora A plays an important role for facilitating acquisition of BCR-ABL mutation and acquired resistance to tyrosine kinase inhibitors in the culture model and suggest that inhibition of Aurora A may provide an alternative strategy to improve CML treatment to overcome resistance.

PROVIDER: S-EPMC3271265 | BioStudies |

REPOSITORIES: biostudies

Similar Datasets

| S-EPMC2836111 | BioStudies
| S-EPMC4072521 | BioStudies
| S-EPMC4245092 | BioStudies
2016-01-01 | S-EPMC5099696 | BioStudies
| S-EPMC3376246 | BioStudies
| S-EPMC2481545 | BioStudies
| S-EPMC2893099 | BioStudies
| S-EPMC5515395 | BioStudies
| S-EPMC3568121 | BioStudies
| E-GEOD-62121 | BioStudies