title: 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.
authors: Department of Cancer Biology, Beckman Research Institute, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
authors: Hongfeng
authors: H
authors: Yuan
authors: Zhiqiang
authors: Z
authors: Wang
authors: Hao
authors: H
authors: Zhang
authors: Mendel
authors: M
authors: Roth
authors: Ravi
authors: R
authors: Bhatia
authors: Wen Yong
authors: WY
authors: Chen
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D064127:Aurora Kinases; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000069439:Dasatinib; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C498826:nilotinib; D000069439:Dasatinib