title: The novel Aurora A kinase inhibitor MLN8237 is active in resistant chronic myeloid leukaemia and significantly increases the efficacy of nilotinib.
abstract: Novel therapies are urgently needed to prevent and treat tyrosine kinase inhibitor resistance in chronic myeloid leukaemia (CML). MLN8237 is a novel Aurora A kinase inhibitor under investigation in multiple phase I and II studies. Here we report that MLN8237 possessed equipotent activity against Ba/F3 cells and primary CML cells expressing unmutated and mutated forms of breakpoint cluster region-Abelson kinase (BCR-ABL). Notably, this agent retained high activity against the T315I and E255K BCR-ABL mutations, which confer the greatest degree of resistance to standard therapy. MLN8237 treatment disrupted cell cycle kinetics, induced apoptosis, caused a dose-dependent reduction in the expression of the large inhibitor of apoptosis protein Apollon, and produced a morphological phenotype consistent with Aurora A kinase inhibition. In contrast to other Aurora kinase inhibitors, MLN8237 did not significantly affect BCR-ABL activity. Moreover, inhibition of Aurora A with MLN8237 significantly increased the in vitro and in vivo efficacy of nilotinib. Targeted knockdown of Apollon sensitized CML cells to nilotinib-induced apoptosis, indicating that this is an important factor underlying MLN8237's ability to increase the efficacy of nilotinib. Our collective data demonstrate that this combination strategy represents a novel therapeutic approach for refractory CML that has the potential to suppress the emergence of T315I mutated CML clones.
authors.affiliation: Department of Medicine, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kelly
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ecsedy
authors.forename: Ernest
authors.initials: E
authors.lastname: Medina
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.forename: Swaminathan
authors.initials: S
authors.lastname: Padmanabhan
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Carew
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D064127:Aurora Kinases; D001381:Azepines / Q000494:pharmacology*; D001549:Benzamides; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology*; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: D001381:Azepines; C401541:BIRC6 protein, human; D001549:Benzamides; D051034:Inhibitor of Apoptosis Proteins; C550258:MLN 8237; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C498826:nilotinib