Definition

An orally bioavailable selective inhibitor of fusion products and mutated forms of the proto-oncogene receptor tyrosine kinase rearranged during transfection (RET), with potential antineoplastic activity. Upon oral administration, the RET inhibitor LOXO-260 selectively binds to and inhibits the activity of RET, including the RET V804 gatekeeper and the G810 solvent-front mutations. This results in an inhibition of cell growth of susceptible tumors cells that exhibit increased RET activity. RET overexpression, activating mutations, and fusions result in the upregulation and/or overactivation of RET tyrosine kinase activity in various cancer cell types; dysregulation of RET activity plays a key role in the development and progression of these cancers. Solvent front and gatekeeper resistance mutations, both individually and when co-expressed, play a key role in acquired tumor resistance to RET inhibitors.