ALK positively regulates MYCN activity through repression of HBP1 expression

Claeys, Shana; Denecker, Geertrui; Durinck, Kaat; Decaesteker, Bieke; Mus, Liselot; Loontiens, Siebe; Vanhauwaert, Suzanne; Althoff, Kristina; Wigerup, Caroline; Bexell, Daniel; Dolman, M. Emmy M.; Henrich, Kai Oliver; Wehrmann, Lea; Westerhout, Ellen M.; Demoulin, Jean‐Baptiste; Kumps, Candy; Maerken, Tom Van; Laureys, Geneviève; Neste, Christophe Van; Wilde, Bram De; Wever, Olivier De; Westermann, Frank; Versteeg, Rogier; Molenaar, Jan J.; Påhlman, Sven; Schulte, Johannes H.; Preter, Katleen De; Speleman, Frank

doi:10.1038/s41388-018-0595-3

Cited by 18 publications

(13 citation statements)

References 73 publications

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“…Cells were seeded in 2 or 3-fold for experiments. Subsequently colonies were allowed to form followed by fixation as previously described 13 . OpenCFU was used to quantify differences in colony forming capacity.…”

Section: Reverse-transcriptase Quantitative Polymerase Chain Reactionmentioning

confidence: 99%

“…One possible mechanism through which ALK mutations may render neuroblastoma more aggressive is through increased MYCN activity resulting from PI 3 K-directed activation of ERK5 transcription levels or inhibiting GSK 3 ß-mediated repression of MYCN protein degradation 11,12 . Further, we recently identified a novel mutant ALK-controlled mechanism driving MYCN activity through PI 3 K/AKT-FOXO3a-controlled downregulation of HBP1, the latter being a negative regulator of MYCN 13 . IRS2 was also recently revealed as an important protein mediating survival through the PI 3 K/AKT-FOXO3 signalling axis 14 .…”

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confidence: 99%

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The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness

Mus

Lambertz

Claeys

et al. 2020

Sci Rep

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neuroblastoma is an aggressive childhood cancer arising from sympatho-adrenergic neuronal progenitors. the low survival rates for high-risk disease point to an urgent need for novel targeted therapeutic approaches. Detailed molecular characterization of the neuroblastoma genomic landscape indicates that ALK-activating mutations are present in 10% of primary tumours. Together with other mutations causing RAS/MAPK pathway activation, ALK mutations are also enriched in relapsed cases and ALK activation was shown to accelerate MYCN-driven tumour formation through hitherto unknown ALK-driven target genes. to gain further insight into how ALK contributes to neuroblastoma aggressiveness, we searched for known oncogenes in our previously reported ALK-driven gene signature. We identified ETV5, a bona fide oncogene in prostate cancer, as robustly upregulated in neuroblastoma cells harbouring ALK mutations, and show high ETV5 levels downstream of the RAS/MAPK axis. Increased ETV5 expression significantly impacted migration, invasion and colony formation in vitro, and ETV5 knockdown reduced proliferation in a murine xenograft model. We also established a gene signature associated with ETV5 knockdown that correlates with poor patient survival. Taken together, our data highlight ETV5 as an intrinsic component of oncogenic ALK-driven signalling through the MApK axis and propose that ETV5 upregulation in neuroblastoma may contribute to tumour aggressiveness. Neuroblastoma is the most common extracranial solid paediatric tumour, accounting for 15% of all childhood cancer deaths and arises from the developing sympathetic nervous system 1. In patients with high-risk disease, 5-year event-free survival is less than 50% 2 , with survivors often suffering from severe side-effects associated with current intensive multi-modal therapies and relapse after first-line therapy 1. Recent sequencing efforts have established the mutational landscape of primary and relapsed neuroblastoma. Primary neuroblastomas, similar to other embryonic tumours, have a very low mutation burden. The 'anaplastic lymphoma kinase' (ALK) tyrosine kinase receptor is the only target with significant recurrent mutations occurring in up to 10% of sporadic cases

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Section: Reverse-transcriptase Quantitative Polymerase Chain Reactionmentioning

confidence: 99%

mentioning

confidence: 99%

The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness

Mus

Lambertz

Claeys

et al. 2020

Sci Rep

Self Cite

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“…A study by Chang et al 117 has demonstrated that high MYCN expression is present in 24 (39.3%) and ALK protein in 25 (41%) of the 61 NB tumors analyzed. A mechanistic study has indicated that ALK plays a role in the positive regulation of MYCN activity through suppression of HMG‐box transcription factor 1 (HBP1) expression in NB cells 118 . Further, large deletions and translocations lead to truncation of the extracellular region of ALK, providing another mechanism of ligand‐independent ALK signaling in NB 119–121 .…”

Section: Major Molecular Pathways Involved In Nb Tumorigenesismentioning

confidence: 99%

Molecular targeting therapies for neuroblastoma: Progress and challenges

Zafar

Wang

Liu

et al. 2020

Medicinal Research Reviews

167

103

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There is an urgent need to identify novel therapies for childhood cancers. Neuroblastoma is the most common pediatric solid tumor, and accounts for ~15% of childhood cancer‐related mortality. Neuroblastomas exhibit genetic, morphological and clinical heterogeneity, which limits the efficacy of existing treatment modalities. Gaining detailed knowledge of the molecular signatures and genetic variations involved in the pathogenesis of neuroblastoma is necessary to develop safer and more effective treatments for this devastating disease. Recent studies with advanced high‐throughput “omics” techniques have revealed numerous genetic/genomic alterations and dysfunctional pathways that drive the onset, growth, progression, and resistance of neuroblastoma to therapy. A variety of molecular signatures are being evaluated to better understand the disease, with many of them being used as targets to develop new treatments for neuroblastoma patients. In this review, we have summarized the contemporary understanding of the molecular pathways and genetic aberrations, such as those in MYCN, BIRC5, PHOX2B, and LIN28B, involved in the pathogenesis of neuroblastoma, and provide a comprehensive overview of the molecular targeted therapies under preclinical and clinical investigations, particularly those targeting ALK signaling, MDM2, PI3K/Akt/mTOR and RAS‐MAPK pathways, as well as epigenetic regulators. We also give insights on the use of combination therapies involving novel agents that target various pathways. Further, we discuss the future directions that would help identify novel targets and therapeutics and improve the currently available therapies, enhancing the treatment outcomes and survival of patients with neuroblastoma.

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“…In adult malignancies, there are data for combinations with BET inhibitors in pre-clinical models and the optimal agent may be disease specific [39e41]; however, there are only modest pre-clinical data available to suggest potential combination partners with BET inhibitors in paediatric cancers. There is pre-clinical synergy between BET inhibitors and PI3K inhibitors in neuroblastoma [42,43] and in some adult tumours [44], and with CDK4/6 inhibitors in medulloblastoma [45].…”

Section: Paediatric Cancer Biology Relevant To Bet Inhibitorsmentioning

confidence: 99%

Bromodomain and extra-terminal inhibitors—A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children—ACCELERATE

Pearson¹,

DuBois

Buenger

et al. 2021

European Journal of Cancer

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Based on biology and pre-clinical data, bromodomain and extra-terminal (BET) inhibitors have at least three potential roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas, MYC/MYCN-driven cancers and fusion-driven malignancies. However, there are now at least 10 BET inhibitors in development, with a limited relevant paediatric population in which to evaluate these medicinal products. Therefore, a meeting was convened with the specific aim to develop a consensus among relevant biopharmaceutical companies, academic researchers, as well as patient and family advocates, about the development of BET inhibitors, including prioritisation and their specific roles in children.Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study (BMS-986158) only opened in 2019. In the future, when there is strong mechanistic rationale or pre-clinical activity of a class of medicinal product in paediatrics, early clinical evaluation with embedded correlative studies of a member of the class should be prioritised and rapidly executed in paediatric populations.There is a strong mechanistic and biological rationale to evaluate BET inhibitors in paediatrics, underpinned by substantial, but not universal, pre-clinical data. However, most pan-BET inhibitors have been challenging to administer in adults, since monotherapy results in only modest anti-tumour activity and provides a narrow therapeutic index due to thrombocytopenia. It was concluded that it is neither scientifically justified nor feasible to undertake simultaneously early clinical trials in paediatrics of all pan-BET inhibitors.However, there is a clinical need for global access to BET inhibitors for patients with NUT carcinoma, a very rare malignancy driven by bromodomain fusions, with proof of concept of clinical benefit in a subset of patients treated with BET inhibitors. Development and regulatory pathway in this indication should include children and adolescents as well as adults.Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous systemepenetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation.This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer.

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ALK positively regulates MYCN activity through repression of HBP1 expression

Cited by 18 publications

References 73 publications

The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness

The ETS transcription factor ETV5 is a target of activated ALK in neuroblastoma contributing to increased tumour aggressiveness

Molecular targeting therapies for neuroblastoma: Progress and challenges

Bromodomain and extra-terminal inhibitors—A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children—ACCELERATE

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