A review of the biological and clinical implications of RAS-MAPK pathway alterations in neuroblastoma

Mlakar, Vid; Morel, Edouard; Mlakar, Simona Jurković; Ansari, Marc; Gumy‐Pause, Fabienne

doi:10.1186/s13046-021-01967-x

Cited by 30 publications

(17 citation statements)

References 134 publications

(205 reference statements)

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“…The results for phosphorylated ERK1/2 contrasted with a previous publication on colorectal cancer cell lines where APR-246 was described as a MEK1/2 inhibitor [20]. ERK1/2 is an end point kinase of the RAS-MAPK pathway, one of the most commonly dysregulated pathways in NB [21]. The RAS-MAPK pathway's signaling branches into PI3K/mTOR/AKT signaling [21] and, thus, an increase in phosphorylated AKT1/2/3 is expected as a consequence of an activated RAS-MAPK pathway.…”

Section: Resultscontrasting

confidence: 98%

“…The RAS-MAPK pathway is currently a high-priority target for pharmacological intervention because it is one of the most frequently deregulated pathways in cancers [21]. Our APR-246 co-treatment experiments with up-stream (alectinib) and down-stream (SCH772984) inhibitors of the RAS-MAPK pathway yielded con icting results.…”

Section: Discussionmentioning

confidence: 80%

“…ERK1/2 is an end point kinase of the RAS-MAPK pathway, one of the most commonly dysregulated pathways in NB [21]. The RAS-MAPK pathway's signaling branches into PI3K/mTOR/AKT signaling [21] and, thus, an increase in phosphorylated AKT1/2/3 is expected as a consequence of an activated RAS-MAPK pathway. To understand whether the dynamics of EKR1/2 phosphorylation could explain the discrepancy between our observations and previous ones, we investigated ERK1/2 protein expression over time (Fig.…”

Section: Resultsmentioning

confidence: 99%

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Neuroblastoma response to RAS-MAPK inhibitors and APR-246 (eprenetapopt) co-treatment is dependent on SLC7A11 phosphorylation.

Mlakar

Oehme

Lesne

et al. 2022

Preprint

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BackgroundWe previously demonstrated that APR-246 could be an e cient treatment option against neuroblastoma (NB), the most common pediatric extracranial solid tumor. APR-246's mechanism of action is not completely understood and can differ between cell types. Here we investigate the involvement of wellknown oncogenic pathways in NB's response to APR-246. MethodsA proteome pro ler kinase assays and western blot analysis were used to identify the molecular pathways involved in the responses to APR-246. Bulk ATP levels were used to determine the viability of cells and the IC50 for APR-246. Cystine-FITC was used to measure the cellular uptake of cysteine. PmRNA5 was used to affect ERK1/2 and pshRNA1 was used to silence HSP27. An IMR-32 xenograft zebra sh embryo model was used to assess APR-246 and sulfasalazine e cacy in vivo. ResultsAfter APR-246 treatment, the most deregulated signaling protein identi ed was ERK1/2, an end-point kinase of the RAS-MAPK pathway. Induction of phospho-ERK1/2 resulted in increased glutathione (GSH) levels, increased cystine uptake and increased resistance of NB cells to APR-246. Using ERK1/2 inhibitors in combination with APR-246, we were able to categorize cells into synergistic and antagonistic groups. After co-treatment, these two groups differ by their levels of SLC7A11 and Hsp27 phosphorylation, cystine uptake and BIM expression. Using erastin and sulfasalazine, both inhibitors of SLC7A11 and activators of ferroptosis, we were able to reverse the antagonistic effects of ERK1/2 inhibitors and demonstrate a strong synergistic action in vitro and in vivo in zebra sh models. ConclusionsThese results demonstrated a pivotal role of the RAS-MAPK pathway in the NB cellular response to APR-246 via the modulation of intracellular concentrations of GSH and the transport of cystine, phosphorylation of Hsp27, and programed cell death. Combining APR-246 with RAS-MAPK pathway inhibitors can, in some cases, lead to antagonistic action, which can be reversed by combining APR-246 with the clinically approved drug sulfasalazine. BackgroundNeuroblastoma (NB) is the most common pediatric extracranial solid tumor. Current event-free survival rates range from 75% to more than 85% for low-and very low-risk groups, to less than 50% for high-risk

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Section: Resultscontrasting

confidence: 98%

Section: Discussionmentioning

confidence: 80%

Section: Resultsmentioning

confidence: 99%

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Neuroblastoma response to RAS-MAPK inhibitors and APR-246 (eprenetapopt) co-treatment is dependent on SLC7A11 phosphorylation.

Mlakar

Oehme

Lesne

et al. 2022

Preprint

Self Cite

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“…In line with this, the expression of the dual-specificity MAPK phosphatase DUSP5 associates with neuroblastoma relapse and poor prognosis ( Aurtenetxe et al, 2018 ). Since activating mutations in components of the RAS/MAPK pathway are frequent in relapsed neuroblastoma ( Huang et al, 2013 ), therapeutic targeting of this pathway is currently being tested in neuroblastoma patients ( Mlakar et al, 2021 ). Whether the KIM-containing classical PTPs may play a physiologic role in the control of MAPK activity in neuroblastomas deserves dedicated analysis.…”

Section: Classical Protein Tyrosine Phosphatases In Neuroblastomamentioning

confidence: 99%

Protein Tyrosine Phosphatases in Neuroblastoma: Emerging Roles as Biomarkers and Therapeutic Targets

Nunes‐Xavier

Zaldumbide

Mosteiro

et al. 2021

Front. Cell Dev. Biol.

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Neuroblastoma is a type of cancer intimately related with early development and differentiation of neuroendocrine cells, and constitutes one of the pediatric cancers with higher incidence and mortality. Protein tyrosine phosphatases (PTPs) are key regulators of cell growth and differentiation by their direct effect on tyrosine dephosphorylation of specific protein substrates, exerting major functions in the modulation of intracellular signaling during neuron development in response to external cues driving cell proliferation, survival, and differentiation. We review here the current knowledge on the role of PTPs in neuroblastoma cell growth, survival, and differentiation. The potential of PTPs as biomarkers and molecular targets for inhibition in neuroblastoma therapies is discussed.

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“…К ним относятся нейрофиброматоз I типа (ген нейрофибромин I), синдром Нунан (Noonan syndrome; ген PTPN11) и синдром Костелло (Costello syndrome; ген HRAS) [32][33][34]. Возникновение злокачественных опухолей у пациентов с сопутствующими RAS-патиями представляет особый интерес, поскольку сигнальный путь RAS-MAPK, по данным недавних исследований, вовлечен в патогенез НБ у пациентов группы высокого риска [35].…”

Section: генетические синдромы ассоциирующиеся с повышенным риском развития нейробластомыunclassified

Key genetic disorders in the pathogenesis of neuroblastoma

Chernysheva

Druy

Kachanov

et al. 2021

Voprosy gematologii/onkologii i immunopatologii v pediatrii

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Neuroblastoma (NB) is a malignant neoplasm of the sympathetic nervous system of embryonic origin, consisting of undifferentiated neuroectodermal cells of the neural crest.In the structure of the incidence of malignant neoplasms in patients under one year of age, NB is the most common tumor. At the same time, mortality of this disease ranks third, behind leukemias and tumors of the central nervous system, and amounts to 13% in the structure of child mortalityfrom malignant tumors in developed countries. The stratification of patients to the risk groups and the subsequent determination of treatment tactics depends on several prognostic factors, including genetic aberrations identified in tumor cells. Moreover, processes such as spontaneous regression and transformation into benign tumors are due to the genetic characteristics of NB. Thus, the study of genetic disorders underlying the pathogenesis of NB is necessary for adequate subdivision of patients into risk groups and developing of new methods of treatment.

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A review of the biological and clinical implications of RAS-MAPK pathway alterations in neuroblastoma

Cited by 30 publications

References 134 publications

Neuroblastoma response to RAS-MAPK inhibitors and APR-246 (eprenetapopt) co-treatment is dependent on SLC7A11 phosphorylation.

Neuroblastoma response to RAS-MAPK inhibitors and APR-246 (eprenetapopt) co-treatment is dependent on SLC7A11 phosphorylation.

Protein Tyrosine Phosphatases in Neuroblastoma: Emerging Roles as Biomarkers and Therapeutic Targets

Key genetic disorders in the pathogenesis of neuroblastoma

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