Alisertib plus induction chemotherapy in previously untreated patients with high-risk, acute myeloid leukaemia: a single-arm, phase 2 trial

Brunner, Andrew M.; Blonquist, Traci M.; DeAngelo, Daniel J.; McMasters, Malgorzata; Fell, Geoffrey; Hermance, Nicole; Winer, Eric S.; Lindsley, R. Coleman; Hobbs, Gabriela; Amrein, Philip C.; Hock, Hanno; Steensma, David P.; Garcia, Jacqueline S.; Luskin, Marlise R.; Stone, Richard; Ballen, Karen K.; Rosenblatt, Jacalyn; Avigan, David; Nahas, Myrna; Mendez, Lourdes M.; McAfee, Steven L.; Moran, Jenna A.; Bergeron, Meghan; Foster, Jared C.; Bertoli, Christina; Manning, Amity L.; McGregor, Kristin; Fishman, Kaitlyn M.; Kuo, Frank C.; Baltay, Michele; Macrae, Molly; Burke, Meghan; Behnan, Tanya T.; Wey, Margaret C.; Som, Tina T.; Ramos, Azucena; Rae, Jessica; Story, Jennifer Lombardi; Nelson, Nicole L.; Logan, Emma; Connolly, Christine; Neuberg, Donna; Chen, Yi Bin; Graubert, Timothy A.; Fathi, Amir T.

doi:10.1016/s2352-3026(19)30203-0

Cited by 24 publications

(14 citation statements)

References 31 publications

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“…In AML, alisertib increases the efficacy of cytarabine in a FOXO-dependent manner [187]. Another two clinical trials have demonstrated that alisertib plus induction chemotherapy with cytarabine and idarubicin is effective and safe in patients with AML [188,189].…”

Section: Combination Therapymentioning

confidence: 99%

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

et al. 2021

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Aurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

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Section: Combination Therapymentioning

confidence: 99%

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

et al. 2021

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“…However, the efficacy of AURKA kinase inhibitors such as Alisertib has been still very poor in clinical trials. 32 , 33 The oncogenic function of AURKA is not completely blocked by the inhibition of its kinase activity, suggesting that AURKA may have non-classical kinase-independent carcinogenicity. Recent studies have shown that AURKA can function biologically in a kinase-independent manner.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4

et al. 2022

Sig Transduct Target Ther

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Aberrant RNA splicing produces alternative isoforms of genes to facilitate tumor progression, yet how this process is regulated by oncogenic signal remains largely unknown. Here, we unveil that non-canonical activation of nuclear AURKA promotes an oncogenic RNA splicing of tumor suppressor RBM4 directed by m6A reader YTHDC1 in lung cancer. Nuclear translocation of AURKA is a prerequisite for RNA aberrant splicing, specifically triggering RBM4 splicing from the full isoform (RBM4-FL) to the short isoform (RBM4-S) in a kinase-independent manner. RBM4-S functions as a tumor promoter by abolishing RBM4-FL-mediated inhibition of the activity of the SRSF1-mTORC1 signaling pathway. Mechanistically, AURKA disrupts the binding of SRSF3 to YTHDC1, resulting in the inhibition of RBM4-FL production induced by the m6A-YTHDC1-SRSF3 complex. In turn, AURKA recruits hnRNP K to YTHDC1, leading to an m6A-YTHDC1-hnRNP K-dependent exon skipping to produce RBM4-S. Importantly, the small molecules that block AURKA nuclear translocation, reverse the oncogenic splicing of RBM4 and significantly suppress lung tumor progression. Together, our study unveils a previously unappreciated role of nuclear AURKA in m6A reader YTHDC1-dependent oncogenic RNA splicing switch, providing a novel therapeutic route to target nuclear oncogenic events.

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“…In a phase 2 trial of patients with castration-resistant and neuroendocrine prostate cancer, a subset of patients with advanced prostate cancer and molecular features supporting Aurora-A and N-myc activation achieved significant clinical benefit from single-agent alisertib (31). Alisertib plus cytarabine and idarubicin induction are effective and safe in acute myeloid leukemia patients (32,33). 60 mg/m 2 alisertib per dose for seven days shows antitumor activity, particularly in neuroblastoma patients with MYCN-nonamplified tumors (34,35).…”

Section: Discussionmentioning

confidence: 99%

“…Alisertib plus cytarabine and idarubicin induction are effective and safe in acute myeloid leukemia patients ( 32 , 33 ). 60 mg/m 2 alisertib per dose for seven days shows antitumor activity, particularly in neuroblastoma patients with MYCN-nonamplified tumors ( 34 , 35 ).…”

Section: Discussionmentioning

confidence: 99%

Aurora Kinase A as a Diagnostic and Prognostic Marker of Malignant Mesothelioma

Guo¹,

Шен

et al. 2021

Front. Oncol.

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BackgroundMalignant mesothelioma (MM) is a highly aggressive cancer with a poor prognosis. Despite the use of several well-known markers, the diagnosis of MM is still challenging in some cases. we applied bioinformatics to identify key genes and screen for diagnostic and prognostic markers of MM.MethodsThe expression profiles of GSE2549 and GSE112154 microarray datasets from the Gene Expression Omnibus database contained 87 cases of MM tissue and 8 cases of normal mesothelial tissue in total. The GEO2R tool was used to detect differentially expressed genes (DEGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of DEGs were performed using DAVID Bioinformatics Resources. The DEGs protein-protein interaction networks were constructed from the STRING database. Cytoscape was used to identify significant modules and hub genes. The GEPIA database was used to explore relationships between hub genes and prognosis of MM. Immunohistochemistry was used to analyze protein expression in tissue microarrays with 47 Chinese MM tissues. Statistical analyses diagnostic and prognostic values.Results346 DEGs were identified: 111 genes upregulated, and 235 downregulated. GO analysis showed that the primary biological processes of these DEGs were cell adhesion, leukocyte migration, and angiogenesis. The main cellular components included the extracellular space, extracellular exosome, and extracellular region. The molecular functions were integrin binding, heparin binding, and calcium ion binding. KEGG pathway analysis showed that DEGs are primarily involved in PPAR signaling pathway, extracellular matrix–receptor interactions, and regulation of lipolysis in adipocytes. Survival analysis showed that seven genes—AURKA, GAPDH, TOP2A, PPARG, SCD, FABP4, and CEBPA—may be potential prognostic markers for MM. Immunohistochemical studies showed that Aurora kinase A (AURKA gene encode, Aurora-A) and GAPDH were highly expressed in MM tissue in comparison with normal mesothelial tissue. Kaplan-Meier analysis confirmed a correlation between Aurora-A protein expression and overall survival but did not confirm a correlation with GAPDH. The receiver operating characteristic curves of Aurora-A protein expression suggested acceptable accuracy (AUC = 0.827; 95% CI [0.6686 to 0.9535]; p = 0.04). The sensitivity and specificity of Aurora-A were 83.33% and 77.78%, respectively.ConclusionAurora-A could be an optimal diagnostic biomarker and a potential prognostic marker for MM.

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Alisertib plus induction chemotherapy in previously untreated patients with high-risk, acute myeloid leukaemia: a single-arm, phase 2 trial

Cited by 24 publications

References 31 publications

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

Nuclear Aurora kinase A switches m6A reader YTHDC1 to enhance an oncogenic RNA splicing of tumor suppressor RBM4

Aurora Kinase A as a Diagnostic and Prognostic Marker of Malignant Mesothelioma

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