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

• 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

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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