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

doi:10.1016/j.xcrm.2022.100686

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

Division of Hematology-Oncology

Producción científica: Article › revisión exhaustiva

4 Citas (Scopus)

Resumen

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.

Idioma original	English (US)
Número de artículo	100686
Publicación	Cell Reports Medicine
Volumen	3
N.º	7
DOI	https://doi.org/10.1016/j.xcrm.2022.100686
Estado	Published - jul 19 2022

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.xcrm.2022.100686

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Estrada-Zuniga, C. M., Cheng, Z. M., Ethiraj, P., Guo, Q., Gonzalez-Cantú, H., Adderley, E., Lopez, H., Landry, B. N., Zainal, A., Aronin, N., Ding, Y., Wang, X., Aguiar, R. C. T., & Dahia, P. L. M. (2022). A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions. Cell Reports Medicine, 3(7), Artículo 100686. https://doi.org/10.1016/j.xcrm.2022.100686

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title = "A RET::GRB2 fusion in pheochromocytoma defies the classic paradigm of RET oncogenic fusions",

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.",

keywords = "GRB2, RET fusion, RET mutation, driver genetic events, oncogenic fusion, paraganglioma, pheochromocytoma, pralsetinib, selpercatinib, tyrosine kinase inhibitor",

author = "Estrada-Zuniga, {Cynthia M.} and Cheng, {Zi Ming} and Purushoth Ethiraj and Qianjin Guo and Hector Gonzalez-Cant{\'u} and Elaina Adderley and Hector Lopez and Landry, {Bethany N.} and Abir Zainal and Neil Aronin and Yanli Ding and Xiaojing Wang and Aguiar, {Ricardo C.T.} and Dahia, {Patricia L.M.}",

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year = "2022",

month = jul,

day = "19",

doi = "10.1016/j.xcrm.2022.100686",

language = "English (US)",

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AU - Estrada-Zuniga, Cynthia M.

AU - Cheng, Zi Ming

AU - Ethiraj, Purushoth

AU - Guo, Qianjin

AU - Gonzalez-Cantú, Hector

AU - Adderley, Elaina

AU - Lopez, Hector

AU - Landry, Bethany N.

AU - Zainal, Abir

AU - Aronin, Neil

AU - Ding, Yanli

AU - Wang, Xiaojing

AU - Aguiar, Ricardo C.T.

AU - Dahia, Patricia L.M.

PY - 2022/7/19

Y1 - 2022/7/19

N2 - 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.

AB - 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.

KW - GRB2

KW - RET fusion

KW - RET mutation

KW - driver genetic events

KW - oncogenic fusion

KW - paraganglioma

KW - pheochromocytoma

KW - pralsetinib

KW - selpercatinib

KW - tyrosine kinase inhibitor

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

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