Selpercatinib combination with the mitochondria-targeted antioxidant MitoQ effectively suppresses RET-mutant thyroid cancer. NPJ Precis Oncol 2024 Feb 20;8(1):39
Date
02/21/2024Pubmed ID
38378752Pubmed Central ID
PMC10879150DOI
10.1038/s41698-024-00536-7Scopus ID
2-s2.0-85185513016 (requires institutional sign-in at Scopus site) 1 CitationAbstract
Genetic alternation of REarranged during Transfection (RET) that leads to constitutive RET activation is a crucial etiological factor for thyroid cancer. RET is known to regulate mitochondrial processes, although the underlying molecular mechanisms remain unclear. We previously showed that the multi-kinase inhibitors vandetanib and cabozantinib increase the mitochondrial membrane potential (Δψm) in RET-mutated thyroid tumor cells and that this effect can be exploited to increase mitochondrial enrichment of Δψm-sensitive agents in the tumor cells. In this study, we hypothesized that the RET-selective inhibitor, selpercatinib, can increase Δψm and, subsequently, tumor cell uptake of the mitochondria-targeted ubiquinone (MitoQ) to the level to break the mitochondrial homeostasis and induce lethal responses in RET-mutated thyroid tumor cells. We show that selpercatinib significantly increased Δψm, and its combination with MitoQ synergistically suppressed RET-mutated human thyroid tumor cells, which we validated using RET-targeted genetic approaches. Selpercatinib and MitoQ, in combination, also suppressed CCDC6-RET fusion cell line xenografts in mice and prolonged animal survival more effectively than single treatments of each agent. Moreover, we treated two patients with CCDC6-RET or RETM918T thyroid cancer, who could not take selpercatinib at regular doses due to adverse effects, with a dose-reduced selpercatinib and MitoQ combination. In response to this combination therapy, both patients showed tumor reduction. The quality of life of one patient significantly improved over a year until the tumor relapsed. This combination of selpercatinib with MitoQ may have therapeutic potential for patients with RET-mutated tumors and intolerant to regular selpercatinib doses.
Author List
Chen W, Dream S, Leung PY, Wu PK, Wong S, Park JIAuthors
Sophie Y. Dream MD Associate Professor in the Surgery department at Medical College of WisconsinJong-In Park PhD Professor in the Biochemistry department at Medical College of Wisconsin
