Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
NPJ precision oncology	8	1	2024 Feb 20	39	NPJ Precis Oncol

URL

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