Combined Mcl-1 and YAP1/TAZ inhibition for treatment of metastatic uveal melanoma.

IF 1.5 4区 医学 Q3 DERMATOLOGY
Melanoma Research Pub Date : 2023-10-01 Epub Date: 2023-07-18 DOI:10.1097/CMR.0000000000000911
Kseniya A Glinkina, Amina F A S Teunisse, Maria Chiara Gelmi, Jelle de Vries, Martine J Jager, Aart G Jochemsen
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引用次数: 0

Abstract

Uveal melanoma is the most common intraocular tumor in adults, representing approximately 5% of all melanoma cases. Up to 50% of uveal melanoma patients develop metastases that are resistant to most of the commonly used antineoplastic treatments. Virtually all uveal melanoma tumors harbor activating mutations in GNAQ or GNA11 , encoding Gαq and Gα11, respectively. Constant activity of these proteins causes deregulation of multiple downstream signaling pathways including PKC, MAPK and YAP1/TAZ. While the importance of YAP1 signaling for the proliferation of uveal melanoma has recently been demonstrated, much less is known about the paralog of YAP1 transcriptional coactivator, named TAZ; however, similar to YAP1, TAZ is expected to be a therapeutic target in uveal melanoma. We performed a small-scale drug screen to discover a compound synergistically inhibiting uveal melanoma proliferation/survival in combination with YAP1/TAZ inhibition. We found that the combination of genetic depletion of YAP1/TAZ together with Mcl-1 inhibition demonstrates a synergistic inhibitory effect on the viability of uveal melanoma cell lines. Similarly, indirect attenuation of the YAP1/TAZ signaling pathway with an inhibitor of the mevalonate pathway, that is, the geranyl-geranyl transferase inhibitor GGTI-298, synergizes with Mcl-1 inhibition. This combination could be potentially used as a treatment for metastatic uveal melanoma.

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Mcl-1和YAP1/TAZ联合抑制治疗转移性葡萄膜黑色素瘤。
葡萄膜黑色素瘤是成人最常见的眼内肿瘤,约占所有黑色素瘤病例的5%。高达50%的葡萄膜黑色素瘤患者发生转移,对大多数常用的抗肿瘤治疗具有耐药性。事实上,所有葡萄膜黑色素瘤肿瘤都有GNAQ或GNA11的激活突变,分别编码Gαq和Gα11。这些蛋白质的持续活性导致包括PKC、MAPK和YAP1/TAZ在内的多种下游信号通路的失调。虽然YAP1信号传导对葡萄膜黑色素瘤增殖的重要性最近已经得到证实,但对YAP1转录辅激活因子TAZ的旁系知之甚少;然而,与YAP1类似,TAZ有望成为葡萄膜黑色素瘤的治疗靶点。我们进行了小规模的药物筛选,发现了一种与YAP1/TAZ抑制联合协同抑制葡萄膜黑色素瘤增殖/存活的化合物。我们发现,YAP1/TAZ的基因缺失与Mcl-1抑制相结合,对葡萄膜黑色素瘤细胞系的生存能力表现出协同抑制作用。类似地,用甲羟戊酸途径的抑制剂,即香叶基-香叶基转移酶抑制剂GGTI-298间接减弱YAP1/TAZ信号通路,与Mcl-1抑制协同作用。这种组合有可能用于治疗转移性葡萄膜黑色素瘤。
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来源期刊
Melanoma Research
Melanoma Research 医学-皮肤病学
CiteScore
3.40
自引率
4.50%
发文量
139
审稿时长
6-12 weeks
期刊介绍: ​​​​​​Melanoma Research is a well established international forum for the dissemination of new findings relating to melanoma. The aim of the Journal is to promote the level of informational exchange between those engaged in the field. Melanoma Research aims to encourage an informed and balanced view of experimental and clinical research and extend and stimulate communication and exchange of knowledge between investigators with differing areas of expertise. This will foster the development of translational research. The reporting of new clinical results and the effect and toxicity of new therapeutic agents and immunotherapy will be given emphasis by rapid publication of Short Communications. ​Thus, Melanoma Research seeks to present a coherent and up-to-date account of all aspects of investigations pertinent to melanoma. Consequently the scope of the Journal is broad, embracing the entire range of studies from fundamental and applied research in such subject areas as genetics, molecular biology, biochemistry, cell biology, photobiology, pathology, immunology, and advances in clinical oncology influencing the prevention, diagnosis and treatment of melanoma.
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