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

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.