Overcoming CML acquired resistance by specific inhibition of Aurora A kinase in the KCL-22 cell model
Menée sur un modèle cellulaire de leucémie myélogène chronique, cette étude suggère que l'inhibition de la protéine kinase Aurora A permettrait de surmonter l'acquisition d'une résistance aux inhibiteurs de tyrosine kinase (imatinib, nilotinib ou dasatinib)
Serine/threonine kinase Aurora A is essential for regulating mammalian cell division and is over-expressed in many types of human cancer. However, the role of Aurora A in chemoresistance of chronic myelogenous leukemia (CML) is not well understood. Using 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.
http://carcin.oxfordjournals.org/content/early/2011/11/24/carcin.bgr278.abstract 2011