Proto-oncogene tyrosine-protein kinase receptor Ret (RET) fusion protein (RET fusion)

Proto-oncogene tyrosine-protein kinase receptor Ret (RET) fusion proteins are oncogenic drivers resulting from chromosomal rearrangements that fuse the 3' portion of the RET gene with a 5' partner gene (PubMed: 32835200). These fusions lead to the constitutive, ligand-independent activation of the RET kinase domain, triggering downstream signaling pathways such as MAPK/ERK, PI3K/AKT, and JAK/STAT that promote uncontrolled cell growth and survival (UniProt: P07949). RET fusions are most prevalent in papillary thyroid cancer (10-20%) and a subset of non-small cell lung cancers (1-2%) (NIH: PDQ Cancer Information). Historically, these were treated with multi-kinase inhibitors, but the development of highly selective RET inhibitors like selpercatinib and pralsetinib has significantly improved clinical outcomes and reduced off-target toxicities (FDA: Retevmo, Gavreto). These targeted therapies specifically bind to the ATP-binding pocket of the RET kinase, effectively shutting down the aberrant signaling driving the malignancy.

Other names

RET fusionRET rearrangementRET-PTCKIF5B-RETCCDC6-RETNCOA4-RETRET chimeric protein

Selective or multi-kinase inhibition of the RET tyrosine kinase domain to prevent constitutive signaling.