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

Anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine-protein kinase ROS (ROS1) are highly homologous receptor tyrosine kinases that play vital roles in cellular signaling regulating growth, survival, and differentiation[4][7]. Normally, their physiological expression is limited, but in cancer, chromosomal rearrangements lead to oncogenic fusion proteins with constitutive kinase activity, driving tumorigenesis in a subset of patients—most notably in non-small cell lung cancer. Both kinases share a similar structure: an extracellular ligand-binding domain, a single-pass transmembrane helix, and a cytoplasmic tyrosine kinase domain[4][7]. Their kinase domains are over 60% identical in sequence and ~84% identical in the ATP-binding site, explaining why some kinase inhibitors are active against both[1][2][5]. Inhibition of these fusion proteins with targeted tyrosine kinase inhibitors has become a standard of care in relevant cancers (e.g., crizotinib, entrectinib, lorlatinib for ALK/ROS1 fusions)[6][7]. However, resistance can develop via secondary mutations within the kinase domains, prompting the need for newer inhibitors and combination therapies[5][7].

Other names

ALKAnaplastic lymphoma kinaseCD246ROS1c-ros oncogene 1proto-oncogene tyrosine-protein kinase ROS

Tyrosine kinase inhibition (competitive ATP binding inhibition leading to suppression of kinase activity, cell cycle arrest, and apoptosis in fusion-positive cancers)