• A RET::GRB2 fusion was found in a pheochromocytoma
• RET retains its kinase domain, swaps the C tail with GRB2, a normal RET binding partner
• RET::GRB2 relies on RET kinase function for transformation
• RET::GRB2 renders cells sensitive to RET inhibitors
The RET kinase receptor targets mutations in neural crest tumors, including pheochromocytomas and oncogenic fusions in epithelial cancers. We report a RET::GRB2 fusion in a pheochromocytoma in which RET, functioning as the upstream partner, retains its kinase domain but loses critical C-terminal motifs and is fused to GRB2, a physiological RET interacting protein. RET::GRB2 is an oncogenic driver that leads to constitutive, ligand-independent RET signaling; has transforming capability dependent on RET catalytic function and is sensitive to RET inhibitors. These observations highlight a new driver event in pheochromocytomas potentially amenable for RET-driven therapy.