A MYC–aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer

Dauch, Daniel; Rudalska, Ramona; Cossa, Giacomo; Nault, Jean–Charles; Kang, Tae‐Won; Wüestefeld, Torsten; Hohmeyer, Anja; Imbeaud, Sandrine; Yevsa, Tetyana; Hoenicke, Lisa; Pantsar, Tatu; Bożko, Przemysław; Malek, Nisar P.; Longerich, Thomas; Laufer, Stefan; Poso, Antti; Zucman‐Rossi, Jessica; Eilers, Martin; Zender, Lars

doi:10.1038/nm.4107

Cited by 213 publications

(196 citation statements)

References 61 publications

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“…ABL could directly activate Myc by phosphorylation on tyrosine 74,54. In addition, we and others demonstrated that AurA promoted tumorigenesis and cell survival by overexpression and stabilization of Myc555657. Since Myc is the common downstream protein of both BCR-ABL and AurA, we proposed the combinational effect of AKI603 and imatinib could be caused by inhibition of Myc.…”

Section: Discussionmentioning

confidence: 81%

Aurora A Kinase Inhibitor AKI603 Induces Cellular Senescence in Chronic Myeloid Leukemia Cells Harboring T315I Mutation

Wang

Chen

et al. 2016

Sci Rep

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The emergence of resistance to imatinib mediated by mutations in the BCR-ABL has become a major challenge in the treatment of chronic myeloid leukemia (CML). Alternative therapeutic strategies to override imatinib-resistant CML are urgently needed. In this study, we investigated the effect of AKI603, a novel small molecule inhibitor of Aurora kinase A (AurA) to overcome resistance mediated by BCR-ABL-T315I mutation. Our results showed that AKI603 exhibited strong anti-proliferative activity in leukemic cells. AKI603 inhibited cell proliferation and colony formation capacities in imatinib-resistant CML cells by inducing cell cycle arrest with polyploidy accumulation. Surprisingly, inhibition of AurA by AKI603 induced leukemia cell senescence in both BCR-ABL wild type and T315I mutation cells. Furthermore, the induction of senescence was associated with enhancing reactive oxygen species (ROS) level. Moreover, the anti-tumor effect of AKI603 was proved in the BALB/c nude mice KBM5-T315I xenograft model. Taken together, our data demonstrate that the small molecule AurA inhibitor AKI603 may be used to overcome drug resistance induced by BCR-ABL-T315I mutation in CML.

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Section: Discussionmentioning

confidence: 81%

Aurora A Kinase Inhibitor AKI603 Induces Cellular Senescence in Chronic Myeloid Leukemia Cells Harboring T315I Mutation

Wang

Chen

et al. 2016

Sci Rep

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“…These findings suggest Myc as a potential therapeutic target for HB. However, MYC does not harbor any cavities into which small molecules can easily bind, indicating Myc oncoproteins are undruggable 5. In addition, small molecule drugs in combination with cytotoxic chemotherapy have not been developed for patients with HB.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐26‐5p functions as a new inhibitor of hepatoblastoma by repressing lin‐28 homolog B and aurora kinase a expression

Zhang

Zhao

et al. 2018

Hepatology Communications

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Hepatoblastoma (HB) is the most common liver tumor in children. Despite recent improvements in treatment strategies, the survival of children with hepatoblastoma remains poor. In this study, we identified a novel role of microRNA‐26a‐5p (miR‐26a‐5p), lin‐28 homolog B (LIN28B), Ras‐related nuclear protein (RAN), and aurora kinase A (AURKA) in HB. The expression of LIN28B, RAN, and AURKA was significantly up‐regulated in human HB livers and cell lines. Knockdown of LIN28B and RAN by small interfering RNAs inhibited HB tumor cell proliferation and foci formation. We also elucidated miR‐26a‐5p‐mediated translational inhibition of LIN28B and AURKA in HB. Overexpression of miR‐26a‐5p markedly decreased LIN28B and AURKA 3′‐untranslated region activities and protein expression and repressed HB cell proliferation and colony formation. In contrast, re‐expression of LIN28B and AURKA rescued miR‐26a‐5p‐mediated suppression of HB cell growth and clonality. Importantly, a decreased miR‐26a‐5p expression correlated with the poor outcome of patients with HB. Conclusion: miR‐26a‐5p is a newly identified repressor of HB growth through its inhibition of the oncogenic LIN28B–RAN–AURKA pathway. (Hepatology Communications 2018;2:481‐491)

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“…Our data confirmed that TEAD4 also regulates MYC (Supplementary Figure S7F, S7G). While there are conflicting data in the literature regarding regulation of MYC by AURKA (53, 59, 60), CDK1 has been shown to regulate both MYCN and MYC (61). Furthermore, it has been reported that TEAD4 binds to the enhancer region of MYC (62), indicating transcriptional regulation as well.…”

Section: Resultsmentioning

confidence: 99%

Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma

et al. 2018

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High-risk neuroblastomas show a paucity of recurrent somatic mutations at diagnosis. As a result, the molecular basis for this aggressive phenotype remains elusive. Recent progress in regulatory network analysis helped us elucidate disease-driving mechanisms downstream of genomic alterations, including recurrent chromosomal alterations. Our analysis identified three molecular subtypes of high-risk neuroblastomas, consistent with chromosomal alterations, and identified subtype-specific master regulator (MR) proteins that were conserved across independent cohorts. A 10–protein transcriptional module – centered around a TEAD4 ↔ MYCN positive-feedback loop – emerged as the regulatory driver of the high-risk subtype associated with MYCN amplification. Silencing of either gene collapsed MYCN-amplified (MYCNAmp) neuroblastoma transcriptional hallmarks and abrogated viability in vitro and in vivo. Consistently, TEAD4 emerged as a robust prognostic marker of poor survival, with activity independent of the canonical Hippo pathway transcriptional co-activators, YAP and TAZ. These results suggest novel therapeutic strategies for the large subset of MYCN deregulated neuroblastomas.

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A MYC–aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer

Cited by 213 publications

References 61 publications

Aurora A Kinase Inhibitor AKI603 Induces Cellular Senescence in Chronic Myeloid Leukemia Cells Harboring T315I Mutation

Aurora A Kinase Inhibitor AKI603 Induces Cellular Senescence in Chronic Myeloid Leukemia Cells Harboring T315I Mutation

MicroRNA‐26‐5p functions as a new inhibitor of hepatoblastoma by repressing lin‐28 homolog B and aurora kinase a expression

Cross-Cohort Analysis Identifies a TEAD4–MYCN Positive Feedback Loop as the Core Regulatory Element of High-Risk Neuroblastoma

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