Mutation-Independent Anaplastic Lymphoma Kinase Overexpression in Poor Prognosis Neuroblastoma Patients

Passoni, Lorena; Longo, Luca; Collini, Paola; Coluccia, Addolorata Maria Luce; Bozzi, Fabio; Podda, Marta; Gregorio, Andrea; Gambini, Claudio; Garaventa, Alberto; Pistoia, Vito; Grosso, Federica; Tonini, Gian Paolo; Cheng, Mangeng; Gambacorti‐Passerini, Carlo; Anichini, Andrea; Fossati-Bellani, Franca; Nicola, Massimo Di; Luksch, Roberto

doi:10.1158/0008-5472.can-08-4419

Cited by 154 publications

(162 citation statements)

References 38 publications

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“…Consequently, in neuroblastomas, highest ALK expression levels (and not moderate levels) were significantly correlated with the most aggressive tumors. 27 Genetic aberrations were only found in a small number of patients in our cohort, suggesting that the majority of ES patients harbor wild-type ALK, although we cannot exclude aberrations outside the investigated domains. Interestingly, three patients harbored sporadic ALK translocations, although the fusion partners and significance of these translocations in a small subset of tumor cells is yet unknown.…”

Section: Discussionmentioning

confidence: 80%

Expression and clinical relevance of MET and ALK in Ewing sarcomas

Fleuren

Roeffen

Leenders

et al. 2013

Intl Journal of Cancer

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Because novel therapeutic options are limited in Ewing sarcomas (ES), we investigated the expression, genetic aberrations and clinical relevance of MET and anaplastic lymphoma kinase (ALK) in ES and determined the relevance of targeting these receptors. MET and ALK protein expression was determined immunohistochemically in 31 (50 samples) and 36 (59 samples) ES patients, respectively. Samples included primary tumors, postchemotherapy resections, metastases and relapses. MET and ALK RTK domains were sequenced in respectively 33 and 32 tumors. Five ES cell lines were treated in vitro with the MET/ALKinhibitor crizotinib, the ALK-inhibitor NVP-TAE684 or the MET-inhibitor cabozantinib and analyzed by MTT assays. Modest to high MET and ALK expression was detected in the majority of ES (86 and 69%, respectively). ALK expression was significantly lower in postchemotherapy resections compared to paired untreated primary tumors (p 5 0.031, z 5 22.310, n 5 11). In primary tumors (n 5 20), membranous MET expression significantly correlated with a poor overall survival (OS) (60 vs. 197 months, p 5 0.014). There was a trend toward a poor event-free survival (67 vs. 111 months, p 5 0.078) and OS (88 vs. 128 months, p 5 0.074) in patients with highest ALK levels (n 5 29). ALK or MET RTK domain aberrations were demonstrated in 5/32 (16%) and 3/33 (9%) tumors, respectively. Crizotinib (IC 50 1.22-3.59 lmol/L), NVP-TAE684 (IC 50 0.15-0.79 lmol/L) and cabozantinib (IC 50 2.69-8.27 lmol/L) affected ES cell viability in vitro. Altogether, our data suggest that MET and ALK are potential novel therapeutic targets in ES and targeting these receptors may be of great interest to rationally design future studies in ES.Ewing sarcoma (ES) is the second most common primary malignant bone tumor occurring in children and adolescents. Although multimodal treatment has improved the prognosis of patients with localized ES during the last decades, the final outcome has not improved for patients with metastatic disease and side effects of treatment could be severe. 1,2 This urges the need for novel therapeutic strategies, including targeted therapies directed against molecules involved in the pathogenesis and progression of ES, 3 Although at present some receptor tyrosine kinases (RTKs) have been implicated in ES, predominantly the insulin-like growth factor-1 receptor (IGF-1R), and to a lesser extent also platelet-derived growth factor receptor (PDGFR) and c-KIT, the role of several other receptors remains to be investigated. 4 In this study, we addressed the role of MET and anaplastic lymphoma kinase (ALK) in ES.MET is a RTK known to be deregulated in many cancers. At present, the hepatocyte growth factor (HGF) is the only known ligand for MET. Upon receptor binding, MET undergoes rapid tyrosine phosphorylation and several intracellular signaling cascades are activated, including the phosphatidylinositol 3 (PI3)/Akt kinase and extracellular signal regulated kinase (Erk) pathways. Several studies have shown that HGF/ MET signaling is involved in c...

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Section: Discussionmentioning

confidence: 80%

Expression and clinical relevance of MET and ALK in Ewing sarcomas

Fleuren

Roeffen

Leenders

et al. 2013

Intl Journal of Cancer

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“…Fusion proteins arising from somatic rearrangements have been reported in anaplastic large cell lymphomas and other tumours (reviewed in [Palmer et al, 2009]). In NB and NB cell lines, both ALK amplification and gain-of-function missense mutations of conserved codons of the TKD have been reported [Chen et al, 2008;George et al, 2008;Janoueix-Lerosey et al, 2008;Passoni et al, 2009]. Some experimental data indicate variable oncogenic potential of ALK mutants with p.F1174L having an increased transforming capacity compared to p.R1275Q and p.K1062M [Chen et al, 2008;De Brouwer et al, 2010].…”

Section: Discussionmentioning

confidence: 99%

Germline gain-of-function mutations of ALK disrupt central nervous system development

et al. 2011

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Neuroblastoma (NB) is a frequent embryonal tumor of sympathetic ganglia and adrenals with extremely variable outcome. Recently, somatic amplification and gainof-function mutations of the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, either somatic or germline, were identified in a significant proportion of NB cases. Here we report a novel syndromic presentation associating congenital NB with severe encephalopathy and abnormal shape of the brainstem on brain MRI in two unrelated sporadic cases harboring de novo, germline, heterozygous ALK gene mutations. Both mutations are gain-of-function mutations that have been reported in NB and NB cell lines. These observations further illustrate the role of oncogenes in both tumour predisposition and normal development, and shed light on the pleiotropic and activity-dependent role of ALK in humans. More generally, missing germline mutations relative to the spectrum of somatic mutations reported for a given oncogene may be a reflection of severe effects during embryonic development, and may prompt mutation screening in patients with extreme phenotypes.

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“…Activating mutations in ALK are found in a large majority of familial cases of neuroblastoma, which account for approximately 2% of all cases of neuroblastoma, and ALK gene mutations or gene amplifications have been identified in up to 15% of sporadic high-risk neuroblastoma cases [19,118]. Furthermore, wild-type ALK expression is elevated in high-risk compared to low-risk neuroblastoma tumors [119]. A subsequent phase I trial using the ALK inhibitor crizotinib in children with relapsed and refractory neuroblastoma has been completed [120], and further studies have identified synergistic combinations of ALK and mTOR inhibitors [121], suggesting a potential role for ALK inhibitors in the treatment of children with tumors with mutant ALK.…”

Section: Treatment -Relapsed and Refractory Neuroblastomamentioning

confidence: 99%

Overview and recent advances in the treatment of neuroblastoma

Whittle

Smith

Doherty

et al. 2017

Expert Review of Anticancer Therapy

300

258

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Introduction: Children with neuroblastoma have widely divergent outcomes, ranging from cure in >90% of patients with low risk disease to <50% for those with high risk disease. Recent research has shed light on the biology of neuroblastoma, allowing for more accurate risk stratification and treatment reduction in many cases, although newer treatment strategies for children with high-risk and relapsed neuroblastoma are needed to improve outcomes. Areas covered: Neuroblastoma epidemiology, diagnosis, risk stratification, and recent advances in treatment of both newly diagnosed and relapsed neuroblastoma. Expert commentary: The identification of newer tumor targets and of novel cell-mediated immunotherapy agents may lead to novel therapeutic approaches, and clinical trials for regimens designed to target individual genetic aberrations in tumors are underway. A combination of therapeutic modalities will likely be required to improve survival and cure rates for patients with high-risk neuroblastoma.ARTICLE HISTORY

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Mutation-Independent Anaplastic Lymphoma Kinase Overexpression in Poor Prognosis Neuroblastoma Patients

Cited by 154 publications

References 38 publications

Expression and clinical relevance of MET and ALK in Ewing sarcomas

Expression and clinical relevance of MET and ALK in Ewing sarcomas

Germline gain-of-function mutations of ALK disrupt central nervous system development

Overview and recent advances in the treatment of neuroblastoma

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