Anaplastic lymphoma kinase (ALK) receptor (ALK)

Anaplastic lymphoma kinase (ALK) receptor is a receptor tyrosine kinase belonging to the insulin receptor superfamily, primarily expressed in the developing central and peripheral nervous systems [UniProt Q9UM73]. In neuroblastoma, ALK acts as a major oncogenic driver through gene amplification or activating point mutations, most commonly R1275Q and F1174L [Mossé et al., Nature, 2008]. The extracellular domain (ECD) of ALK is particularly significant in neuroblastoma as it remains intact and accessible on the cell surface, unlike the truncated fusion proteins typically found in other cancers like non-small cell lung cancer [Carpenter and Mossé, Frontiers in Oncology, 2014]. This accessibility makes the ALK ECD a prime target for novel immunotherapeutic strategies, including monoclonal antibodies, antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies [ClinicalTrials.gov]. While traditional small-molecule tyrosine kinase inhibitors (TKIs) like crizotinib and lorlatinib target the intracellular catalytic domain, therapies directed at the ECD offer a way to bypass kinase-domain resistance mutations [PubMed PMID: 28811435]. By binding to the receptor, these agents can either block ligand-induced activation or facilitate immune-mediated destruction of the neuroblastoma cells [PubMed PMID: 21693593]. Consequently, ALK remains a central focus for precision medicine in high-risk neuroblastoma patients.

Other names

CD246ALK tyrosine kinase receptorAnaplastic lymphoma receptor tyrosine kinase

Inhibition of the intracellular tyrosine kinase domain to block downstream signaling pathways (PI3K/AKT, MAPK/ERK, JAK/STAT) or direct binding to the extracellular domain to trigger immune-mediated cell death or internalization of cytotoxic payloads [PubMed PMID: 28811435].