Evolution of Resistance to Aurora Kinase B Inhibitors in Leukaemia Cells

Failes, Timothy W.; Mitic, Gorjana; Abdel-Halim, Heba; Po'uha, Sela T.; Liu, Marjorie; Hibbs, David E.; Kavallaris, Maria

doi:10.1371/journal.pone.0030734

Cited by 16 publications

(8 citation statements)

References 31 publications

(39 reference statements)

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“…In addition, the effect of VE‐465 or VX‐680 for inducing apoptosis in MLL‐AF4 ‐positive RS4;11 and MV4;11 cells seems to have occurred through the inhibition of Aurora‐A. To further confirm this phenomenon, we tested the effect of the Aurora‐A‐specific inhibitor, MLN8237, and the Aurora‐B‐specific inhibitor, ZM447439, in MLL‐AF4 ‐positive ALL cells . The results further support our conclusion that the Aurora kinase inhibitors, VE‐465 and VX‐680, lead MLL‐AF4 ‐positive ALL cells to undergo apoptosis through the inhibition of Aurora‐A (Fig.…”

Section: Discussionsupporting

confidence: 70%

CDKN1A-mediated responsiveness ofMLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors

et al. 2014

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Overexpression of Aurora kinases is largely observed in many cancers, including hematologic malignancies. In this study, we investigated the effects and molecular mechanisms of Aurora kinase inhibitors in acute lymphoblastic leukemia (ALL). Western blot analysis showed that both Aurora‐A and Aurora‐B are overexpressed in ALL cell lines and primary ALL cells. Both VE‐465 and VX‐680 effectively inhibited Aurora kinase activities in nine ALL cell lines, which exhibited different susceptibilities to the inhibitors. Cells sensitive to Aurora kinase inhibitors underwent apoptosis at an IC50 of ∼10–30 nM and displayed a phenotype of Aurora‐A inhibition, whereas cells resistant to Aurora kinase inhibitors (with an IC50 more than 10 μM) accumulated polyploidy, which may have resulted from Aurora‐B inhibition. Drug susceptibility of ALL cell lines was not correlated with the expression level or activation status of Aurora kinases. Interestingly, RS4;11 and MV4;11 cells, which contain the MLL‐AF4 gene, were both sensitive to Aurora kinase‐A inhibitors treatment. Complementary DNA (cDNA) microarray analysis suggested that CDKN1A might govern the drug responsiveness of ALL cell lines in a TP53‐independent manner. Most importantly, primary ALL cells with MLL‐AF4 and CDKN1A expression were sensitive to Aurora kinase inhibitors. Our study suggests CDKN1A could be a potential biomarker in determining the drug responsiveness of Aurora kinase inhibitors in ALL, particularly in MLL‐AF4‐positive patients.

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Section: Discussionsupporting

confidence: 70%

CDKN1A-mediated responsiveness ofMLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors

et al. 2014

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“…Despite the initial promise of aurora kinase inhibition for treatment of patients with leukemia, 6,7,9 recent findings also point to new independent mechanisms of resistance to therapy, 15 and the clinical utility of this group of agents, at least as monotherapy, remains unproven.…”

Section: Discussionmentioning

confidence: 99%

A Phase I and Pharmacodynamic Study of AT9283, a Small-Molecule Inhibitor of Aurora Kinases in Patients With Relapsed/Refractory Leukemia or Myelofibrosis

Foran

Ravandi

Wierda

et al. 2014

Clinical Lymphoma Myeloma and Leukemia

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Purpose To identify the MTD of AT9283, an inhibitor of Aurora kinases A and B, in patients with relapsed or refractory leukemias. Other endpoints included pharmacokinetics, safety and tolerability, pharmacodynamics and preliminary evidence of efficacy. Patients and Methods AT9283 was administered as a continuous 72h infusion every 21 days. Doses were escalated by a standard 3+3 design. After the MTD for the 72h infusion was identified, infusion duration was increased incrementally to 96h and 120h. In total, 48 patients received ≥1 cycle of AT9283. Median age was 61 years (range 22–86 years), with 56% men, 75% diagnosed with AML, and 89% having received ≥3 (up to 16) prior lines of therapy. Results 324 mg/m2/72h AT9283 was determined to be the MTD. DLTs were myocardial infarction, hypertension, cardiomyopathy, tumor lysis syndrome, pneumonia and multiorgan failure. Other AT9283-related toxicities (non-DLT) included myelosuppression, predominantly leucopenia and mucositis. Bone marrow blasts decreased ≥38% after AT9283 treatment in approximately one-third of patients with relapsed/refractory AML; however, this effect was transient and no objective responses were achieved, despite evidence of aurora kinase B inhibition. Two patients with accelerated phase CML showed evidence of benefit, manifest as a cytogenetic response in one case; one patient completed 6 cycles of treatment. Exposure to AT9283 was generally dose proportional. Conclusion AT9283 tolerability was strongly dose dependent with reversible myelosuppression predominating at lower doses and events such as cardiovascular toxicities manifesting at higher doses. Clinical trials with AT9283 are ongoing in alternative patient populations.

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“…Interestingly, the HBCx-17 xenograft that carries mutations in both p53 and BRCA2 genes (15) was moderately sensitive to AS703569, suggesting that a combination of these factors might not be sufficient to increase sensitivity to Aurora kinase inhibitors, as it was shown in vitro (26). General mechanisms of tumor cell resistance to Aurora kinase inhibitors have not been identified yet, although in vitro studies suggest that mutations of the targeted Aurora kinases and overexpression of drug resistance genes may be involved (27,28).…”

Section: Discussionmentioning

confidence: 99%

Inhibiting Aurora Kinases Reduces Tumor Growth and Suppresses Tumor Recurrence after Chemotherapy in Patient-Derived Triple-Negative Breast Cancer Xenografts

Romanelli

Clark

Assayag

et al. 2012

Molecular Cancer Therapeutics

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Triple-negative breast cancers (TNBC) have an aggressive phenotype with a relatively high rate of recurrence and poor overall survival. To date, there is no approved targeted therapy for TNBCs. Aurora kinases act as regulators of mammalian cell division. They are important for cell-cycle progression and are frequently overexpressed or mutated in human tumors, including breast cancer. In this study, we investigated the therapeutic potential of targeting Aurora kinases in preclinical models of human breast cancers using a paninhibitor of Aurora kinases, AS703569. In vitro, AS703569 was tested in 15 human breast cancer cell lines. TNBC cell lines were more sensitive to AS703569 than were other types of breast cancer cells. Inhibition of proliferation was associated with cell-cycle arrest, aneuploidy, and apoptosis. In vivo, AS703569 administered alone significantly inhibited tumor growth in seven of 11 patient-derived breast cancer xenografts. Treatment with AS703569 was associated with a decrease of phospho-histone H3 expression. Finally, AS703569 combined to doxorubicin-cyclophosphamide significantly inhibited in vivo tumor recurrence, suggesting that Aurora kinase inhibitors could be used both in monotherapy and in combination settings. In conclusion, these data indicate that targeting Aurora kinases could represent a new effective approach for TNBC treatment. Mol Cancer Ther; 11(12); 2693-703. Ó2012 AACR.

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Evolution of Resistance to Aurora Kinase B Inhibitors in Leukaemia Cells

Cited by 16 publications

References 31 publications

CDKN1A-mediated responsiveness ofMLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors

CDKN1A-mediated responsiveness ofMLL-AF4-positive acute lymphoblastic leukemia to Aurora kinase-A inhibitors

A Phase I and Pharmacodynamic Study of AT9283, a Small-Molecule Inhibitor of Aurora Kinases in Patients With Relapsed/Refractory Leukemia or Myelofibrosis

Inhibiting Aurora Kinases Reduces Tumor Growth and Suppresses Tumor Recurrence after Chemotherapy in Patient-Derived Triple-Negative Breast Cancer Xenografts

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