Anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) (ALK/ROS1)

Anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1) are closely related receptor tyrosine kinases belonging to the insulin receptor superfamily [1, 4]. They share significant structural homology, particularly within their intracellular kinase domains, which enables many small-molecule inhibitors to target both proteins effectively [3, 5]. In a physiological context, ALK is involved in the development and maintenance of the nervous system, while ROS1 is thought to play a role in cell growth and differentiation [2, 10]. Pathologically, these kinases frequently undergo chromosomal rearrangements that result in oncogenic fusion proteins, such as EML4-ALK and CD74-ROS1, which drive constitutive signaling and uncontrolled cell proliferation [6, 12]. These fusions are most notably found in a subset of non-small cell lung cancers (NSCLC), as well as in anaplastic large cell lymphoma and inflammatory myofibroblastic tumors [1, 7]. Therapeutic targeting with tyrosine kinase inhibitors (TKIs) like crizotinib, alectinib, and lorlatinib has significantly improved outcomes for patients with these genetic alterations [8, 9]. However, the emergence of resistance mutations, such as the ALK G1202R and ROS1 G2032R 'gatekeeper' mutations, remains a major clinical challenge in long-term management [12, 16].

Other names

ALKROS1CD246ROSMCF3NBLST3c-ros oncogene 1Anaplastic lymphoma receptor tyrosine kinase

Tyrosine kinase inhibition via ATP-competitive binding to the intracellular kinase domain, preventing autophosphorylation and downstream oncogenic signaling.