Cell Reports Medicine: A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions (Wang)

Cynthia M.Estrada-Zuniga18  Zi-MingCheng18  PurushothEthiraj18  QianjinGuo1  HectorGonzalez-Cantú1  ElainaAdderley2  HectorLopez1  Bethany N.Landry1  AbirZainal2  NeilAronin2  YanliDing3  XiaojingWang45  Ricardo C.T.Aguiar167  Patricia L.M.Dahia169

Highlights

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

Summary

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.

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