A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions

The RET kinase receptor is a target of mutations in neural crest tumors, including pheochromocytomas, and of 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 pheochromo-cytomas potentially amenable for RET-driven therapy.

Automated summary

This study reports a RET::GRB2 fusion in pheochromocytoma, which functions as an oncogenic driver and is sensitive to RET inhibitors, providing a new potential target for therapy in pheochromocytoma.