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Ref Type Journal Article
PMID (38378752)
Authors Chen W, Dream S, Leung PY, Wu PK, Wong S, Park JI
Title Selpercatinib combination with the mitochondria-targeted antioxidant MitoQ effectively suppresses RET-mutant thyroid cancer.
Abstract Text 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.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
MitoQ MitoQ 0 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
MitoQ mitoquinone MitoQ is a mitochondria-targeted ubiquinone derivative, which may decrease tumor cell viability and tumor growth (PMID: 38378752, PMID: 11092892).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET M918T thyroid gland medullary carcinoma sensitive MitoQ + Selpercatinib Case Reports/Case Series Actionable In a clinical case study, treatment with the combination of Retevmo (selpercatinib) and MitoQ resulted in a partial response in a patient with medullary thyroid cancer harboring RET M918T, and in preclinical analysis, synergistically inhibited viability of a medullary thyroid cancer cell line harboring RET M918T in culture (PMID: 38378752). 38378752
RET C634W thyroid gland medullary carcinoma sensitive MitoQ + Selpercatinib Preclinical - Cell culture Actionable In a preclinical study, the combination of Retevmo (selpercatinib) and MitoQ synergistically inhibited viability of a medullary thyroid cancer cell line harboring RET C634W in culture (PMID: 38378752). 38378752