ALK, ROS1, MET/HGFR, and RON

Class

Multi-target tyrosine kinase inhibitor (ALK/ROS1/MET inhibitor)

Pathway

ATP-competitive small-molecule inhibition of ALK, ROS1, and c-MET/HGFR receptor tyrosine kinases and their oncogenic fusion/mutant variants

ALK (anaplastic lymphoma kinase), ROS1, and MET (also called HGFR, the hepatocyte growth factor receptor) are receptor tyrosine kinases—membrane enzymes that, once switched on, relay growth and survival signals into a cell. RON is a related receptor sharing structural similarity with MET. In certain cancers, chromosomal rearrangements fuse the ALK or ROS1 gene to an unrelated partner gene, creating a fusion protein that signals continuously without needing an external trigger. MET can become abnormally active through gene amplification, mutation, or fusion, driving similar unchecked proliferation. A single inhibitor that blocks ALK, ROS1, MET, and RON together is useful because tumors driven by any one of these alterations can be treated with the same agent, and because some tumors carry more than one alteration or shift their dependency between these related kinases over time. These inhibitors occupy the ATP-binding pocket of the kinase, preventing it from transferring phosphate groups to downstream proteins and thereby interrupting signaling cascades—chiefly RAS-MAPK and PI3K-AKT—that promote cell division and block programmed cell death. This mechanism is broadly relevant across solid tumors, most notably non-small cell lung cancer, where ALK and ROS1 fusions and MET alterations define distinct molecular subsets of disease.