Selpercatinib combination with the mitochondria-targeted antioxidant MitoQ effectively suppresses RET-mutant thyroid
Wenjing Chen1, Sophie Dream2, Pui-Yin Leung1
1Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Abstract:
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.
Insights
Selpercatinib and MitoQ synergistically suppress RET-mutated thyroid cancer cells by increasing mitochondrial membrane potential (Δψm). This combination therapy shows promise for patients intolerant to standard selpercatinib doses.
Area of Science:
- Oncology
- Molecular Biology
- Mitochondrial Biology
Background:
- Constitutive activation of REarranged during Transfection (RET) is a key driver in thyroid cancer.
- RET signaling influences mitochondrial function, but mechanisms are not fully understood.
- Previous studies showed multi-kinase inhibitors increase mitochondrial membrane potential (Δψm) in RET-mutated thyroid cells.
Purpose of the Study:
- To investigate if the RET-selective inhibitor selpercatinib increases Δψm.
- To determine if combining selpercatinib with mitochondria-targeted ubiquinone (MitoQ) induces lethal responses in RET-mutated thyroid tumor cells.
- To evaluate the therapeutic potential of selpercatinib and MitoQ combination in preclinical models and patients.
Main Methods:
- Treatment of RET-mutated thyroid tumor cells with selpercatinib and/or MitoQ.
- Measurement of mitochondrial membrane potential (Δψm).
- Assessment of synergistic effects on cell viability using RET-targeted genetic approaches.
- Evaluation in CCDC6-RET fusion cell line xenografts in mice.
- Clinical application in two patients with RET-mutated thyroid cancer.
Main Results:
- Selpercatinib significantly increased Δψm in RET-mutated thyroid tumor cells.
- The combination of selpercatinib and MitoQ synergistically suppressed these cells.
- Combination therapy suppressed xenograft tumors in mice and prolonged survival.
- Two patients with RET-mutated thyroid cancer showed tumor reduction with dose-reduced selpercatinib and MitoQ, with one experiencing improved quality of life.
Conclusions:
- Selpercatinib enhances mitochondrial function, and its combination with MitoQ offers a synergistic therapeutic strategy for RET-mutated thyroid cancer.
- This combination may be particularly beneficial for patients intolerant to standard selpercatinib doses.
- The findings support further investigation of selpercatinib and MitoQ as a novel treatment for RET-driven thyroid cancers.
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