Activation of DCTN1-RET Fusion Through Coiled-coil Domain as a Potential Target for RET Inhibitors.

Abstract

Background/aim: The REarranged during Transfection (RET) proto-oncogene fusion is a typical cancer driver gene frequently observed in thyroid and lung cancers. This study characterized the novel dynactin subunit 1 (DCTN1)-RET fusion gene and evaluated the efficacy of RET inhibitors against this fusion.

Materials and methods: Thyroid cancer tissue DNA samples were sequenced to identify fusion genes, and an expression vector was generated using extracted RNA. Cell lines stably expressing DCTN1-RET variants, including those lacking the coiled-coil (CC) domain, were established. The functionality of these variants and therapeutic efficacy of RET inhibitors were examined both in vitro and in vivo.

Results: The DCTN1-RET fusion gene contains the CC domain from DCTN1 and the kinase domain from RET. Deletion of the CC domain abrogated dimer formation and reduced RET and extracellular signal-regulated kinase phosphorylation. Cells expressing DCTN1-RET exhibited enhanced proliferation and tumorigenesis in vivo. The RET inhibitor TAS0286 effectively suppressed DCTN1-RET-mediated RET autophosphorylation and tumor growth in a mouse subcutaneous tumor model.

Conclusion: DCTN1-RET is a novel oncogenic fusion gene in thyroid cancer that promotes tumorigenesis through CC domain-mediated dimerization. It represents a potential therapeutic target for RET-specific inhibitors.