Integrated proximal proteomics reveals IRS2 as a determinant of cell survival in ALK-driven neuroblastoma

Oncogenic anaplastic lymphoma kinase (ALK) is one of the few druggable targets in neuroblastoma, and therapy resistance to ALK-targeting tyrosine kinase inhibitors (TKIs) comprises an inevitable clinical challenge. Therefore, a better understanding of the oncogenic signaling network rewiring driven by ALK is necessary to improve and guide future therapies. Here, we performed quantitative mass spectrometry–based proteomics on neuroblastoma cells treated with one of three clinically relevant ALK TKIs (crizotinib, LDK378, or lorlatinib) or an experimentally used ALK TKI (TAE684) to unravel aberrant ALK signaling pathways. Our integrated proximal proteomics (IPP) strategy included multiple signaling layers, such as the ALK interactome, phosphotyrosine interactome, phosphoproteome, and proteome. We identified the signaling adaptor protein IRS2 (insulin receptor substrate 2) as a major ALK target and an ALK TKI–sensitive signaling node in neuroblastoma cells driven by oncogenic ALK. TKI treatment decreased the recruitment of IRS2 to ALK and reduced the tyrosine phosphorylation of IRS2. Furthermore, siRNA-mediated depletion of ALK or IRS2 decreased the phosphorylation of the survival-promoting kinase Akt and of a downstream target, the transcription factor FoxO3, and reduced the viability of three ALK-driven neuroblastoma cell lines. Collectively, our IPP analysis provides insight into the proximal architecture of oncogenic ALK signaling by revealing IRS2 as an adaptor p...
Source: Signal Transduction Knowledge Environment - Category: Science Authors: Tags: STKE Research Resources Source Type: news

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Conditions:   Hematopoietic and Lymphoid Cell Neoplasm;   Recurrent Ependymoma;   Recurrent Ewing Sarcoma;   Recurrent Hepatoblastoma;   Recurrent Histiocytic and Dendritic Cell Neoplasm;   Recurrent Langerhans Cell Histiocytosis;   Recurrent Lymphoma;   Recurrent Malignant Germ Cel l Tumor;   Recurrent Malignant Glioma;   Recurrent Malignant Solid Neoplasm;   Recurrent Medulloblastoma;   Recurrent Neuroblastoma;   Recurr...
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
Abstract On March 28, 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion recommending the marketing authorization for the medicinal product plerixafor. The marketing authorization holder for this medicinal product is Genzyme Europe B.Th. The adoption was for an extension of the existing adult indication in combination with granulocyte colony-stimulating factor (G-CSF) to pediatric patients (aged 1 year to
Source: The Oncologist - Category: Cancer & Oncology Authors: Tags: Oncologist Source Type: research
Sinonasal malignancies characterised by cells with a round to rhabdoid morphology offer a diagnostic challenge. Biopsies are often limited, and tumours can share several overlapping morphological and immunophenotypic features. Carcinomas, lymphomas, sarcomas and neuroblastomas falling into this category are reviewed here with an emphasis on the diagnostic pitfalls that can exist in immunohistochemistry and cytogenetic results.
Source: Diagnostic Histopathology - Category: Pathology Authors: Tags: Mini-symposium: Head and neck pathology Source Type: research
Conditions:   Ectomesenchymoma;   Recurrent Adrenal Gland Pheochromocytoma;   Recurrent Ependymoma;   Recurrent Ewing Sarcoma;   Recurrent Hepatoblastoma;   Recurrent Langerhans Cell Histiocytosis;   Recurrent Malignant Germ Cell Tumor;   Recurrent Malignant Glioma;   Recurrent Medull oblastoma;   Recurrent Melanoma;   Recurrent Neuroblastoma;   Recurrent Non-Hodgkin Lymphoma;   Recurrent Osteosarcoma;   Recurrent Peripheral Primitive Neuroectode...
Source: ClinicalTrials.gov - Category: Research Source Type: clinical trials
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