Chen Wenjing, Dream Sophie, Leung Pui-Yin, Wu Pui-Kei, Wong Stuart, Park Jong-In
Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
NPJ Precis Oncol. 2024 Feb 20;8(1):39. doi: 10.1038/s41698-024-00536-7.
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 (Δψ) in RET-mutated thyroid tumor cells and that this effect can be exploited to increase mitochondrial enrichment of Δψ-sensitive agents in the tumor cells. In this study, we hypothesized that the RET-selective inhibitor, selpercatinib, can increase Δψ 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 Δψ, 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 RET 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.
转染过程中重排（RET）的基因改变导致RET组成性激活，是甲状腺癌的关键病因。已知RET可调节线粒体过程，但其潜在分子机制尚不清楚。我们之前表明，多激酶抑制剂凡德他尼和卡博替尼可增加RET突变甲状腺肿瘤细胞的线粒体膜电位（Δψ），并且这种效应可用于增加肿瘤细胞中对Δψ敏感药物的线粒体富集。在本研究中，我们假设RET选择性抑制剂塞尔帕替尼可增加Δψ，随后增加线粒体靶向泛醌（MitoQ）对肿瘤细胞的摄取，达到破坏线粒体稳态并在RET突变甲状腺肿瘤细胞中诱导致死反应的水平。我们表明，塞尔帕替尼显著增加Δψ，其与MitoQ联合使用可协同抑制RET突变的人甲状腺肿瘤细胞，我们使用靶向RET的基因方法对此进行了验证。塞尔帕替尼和MitoQ联合使用还可抑制小鼠CCDC6-RET融合细胞系异种移植瘤，并比单一药物治疗更有效地延长动物生存期。此外，我们对两名因不良反应无法常规剂量服用塞尔帕替尼的CCDC6-RET或RET甲状腺癌患者，采用剂量降低的塞尔帕替尼和MitoQ联合治疗。针对这种联合治疗，两名患者均出现肿瘤缩小。一名患者的生活质量在肿瘤复发前的一年中显著改善。塞尔帕替尼与MitoQ的这种联合使用可能对RET突变肿瘤且无法耐受常规塞尔帕替尼剂量的患者具有治疗潜力。
