Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health San Antonio (UTHSA), San Antonio, TX, USA.
Division of Endocrinology, University of Massachusetts Worcester, Worcester, MA, USA.
Cell Rep Med. 2022 Jul 19;3(7):100686. doi: 10.1016/j.xcrm.2022.100686.
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.
RET 激酶受体是神经嵴肿瘤（包括嗜铬细胞瘤）中突变的靶点，也是上皮性癌症中致癌融合的靶点。我们报告了一例嗜铬细胞瘤中存在 RET::GRB2 融合，其中 RET 作为上游伙伴，保留了其激酶结构域，但失去了关键的 C 端基序，并与 GRB2 融合，GRB2 是一种生理上与 RET 相互作用的蛋白质。RET::GRB2 是一种致癌驱动基因，导致配体非依赖性的 RET 信号的持续激活；具有依赖于 RET 催化功能的转化能力；并对 RET 抑制剂敏感。这些观察结果突出了一种新的驱动事件，可能使嗜铬细胞瘤适合 RET 驱动的治疗。
