Anaplastic lymphoma kinase (ALK) (ALK)

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase and a member of the insulin receptor superfamily [1]. While its physiological expression is primarily restricted to the developing nervous system, where it plays a role in neuronal differentiation and synapse formation, ALK is a major oncogenic driver in several human cancers [1, 2]. It was first identified as part of the NPM-ALK fusion protein in anaplastic large cell lymphoma (ALCL) and has since been recognized as a critical therapeutic target in non-small cell lung cancer (NSCLC) through the EML4-ALK rearrangement [3, 4]. Oncogenic activation typically occurs via chromosomal translocations that create fusion proteins with constitutive kinase activity, though gene amplification and point mutations also occur, particularly in neuroblastoma [2]. Several generations of ALK-targeted tyrosine kinase inhibitors (TKIs), such as crizotinib, alectinib, and lorlatinib, have been developed to block the receptor's signaling, which otherwise activates downstream pathways like PI3K/AKT and MAPK to promote cell survival and proliferation [5]. Despite the success of these therapies, the development of resistance mutations in the kinase domain remains a primary challenge in long-term clinical management [4].

Other names

CD246Anaplastic lymphoma receptor tyrosine kinaseALK tyrosine kinase receptorKi-1

Small molecule inhibitors compete with ATP for binding to the intracellular tyrosine kinase domain of the ALK receptor, preventing autophosphorylation and the activation of downstream signaling pathways such as PI3K/AKT, MAPK/ERK, and JAK/STAT [1, 5].