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
RET	L633V	missense	unknown	RET L633V lies within the extracellular domain of the Ret protein (UniProt.org). L633V has been identified in the scientific literature (PMID: 30446652, PMID: 38378752), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Aug 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RET M918T	medullary thyroid 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	medullary thyroid 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