Anaplastic lymphoma kinase (ALK) R1275Q mutant (ALK R1275Q)

The Anaplastic lymphoma kinase (ALK) R1275Q mutant is a constitutively active form of the ALK receptor tyrosine kinase, resulting from a point mutation in the kinase domain [1, 3]. This specific mutation is the most frequent ALK alteration found in both familial and sporadic neuroblastoma, a common pediatric solid tumor [4, 9]. The R1275Q substitution leads to ligand-independent auto-phosphorylation and subsequent activation of downstream oncogenic signaling pathways, including PI3K-AKT, RAS-MAPK, and JAK-STAT, which promote cell proliferation and survival [3, 10, 11]. Clinically, the R1275Q mutant is significant because it remains relatively sensitive to first-generation ALK inhibitors like crizotinib, unlike other common mutations such as F1174L [1, 8, 10]. However, next-generation inhibitors like ceritinib and lorlatinib are also employed to achieve more potent inhibition and overcome potential resistance [6, 8, 11]. Identifying this mutation serves as a critical biomarker for selecting patients for targeted therapy in neuroblastoma management [5, 6, 8].

Other names

CD246 [1]ALK tyrosine kinase receptor [1, 11]Anaplastic lymphoma receptor tyrosine kinase [6, 9]NBLST3 [9]

Tyrosine kinase inhibition [1, 3, 4, 12]