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

Cynthia M. Estrada-Zuniga, Zi Ming Cheng, Purushoth Ethiraj, Qianjin Guo, Hector Gonzalez-Cantú, Elaina Adderley, Hector Lopez, Bethany N. Landry, Abir Zainal, Neil Aronin, Yanli Ding, Xiaojing Wang, Ricardo C.T. Aguiar, Patricia L.M. Dahia

Research output: Contribution to journalArticlepeer-review

Abstract

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 pheochromocytomas potentially amenable for RET-driven therapy.

Original languageEnglish (US)
Article number100686
JournalCell Reports Medicine
Volume3
Issue number7
DOIs
StatePublished - Jul 19 2022

Keywords

  • GRB2
  • RET fusion
  • RET mutation
  • driver genetic events
  • oncogenic fusion
  • paraganglioma
  • pheochromocytoma
  • pralsetinib
  • selpercatinib
  • tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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