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鉴定维莫非尼耐药黑素瘤细胞系揭示了靶向治疗耐药的新特征。

Characterization of Vemurafenib-Resistant Melanoma Cell Lines Reveals Novel Hallmarks of Targeted Therapy Resistance.

机构信息

Laboratory for Protein Dynamics, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia.

School of Medicine, Catholic University of Croatia, 10000 Zagreb, Croatia.

出版信息

Int J Mol Sci. 2022 Aug 31;23(17):9910. doi: 10.3390/ijms23179910.

DOI:10.3390/ijms23179910
PMID:36077308
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9455970/
Abstract

Regardless of the significant improvements in treatment of melanoma, the majority of patients develop resistance whose mechanisms are still not completely understood. Hence, we generated and characterized two melanoma-derived cell lines, primary WM793B and metastatic A375M, with acquired resistance to the RAF inhibitor vemurafenib. The morphology of the resistant primary WM793B melanoma cells showed EMT-like features and exhibited a hybrid phenotype with both epithelial and mesenchymal characteristics. Surprisingly, the vemurafenib-resistant melanoma cells showed a decreased migration ability but also displayed a tendency to collective migration. Signaling pathway analysis revealed the reactivation of MAPK and the activation of the PI3K/AKT pathway depending on the vemurafenib-resistant cell line. The acquired resistance to vemurafenib caused resistance to chemotherapy in primary WM793B melanoma cells. Furthermore, the cell-cycle analysis and altered levels of cell-cycle regulators revealed that resistant cells likely transiently enter into cell cycle arrest at the G0/G1 phase and gain slow-cycling cell features. A decreased level of NME1 and NME2 metastasis suppressor proteins were found in WM793B-resistant primary melanoma, which is possibly the result of vemurafenib-acquired resistance and is one of the causes of increased PI3K/AKT signaling. Further studies are needed to reveal the vemurafenib-dependent negative regulators of NME proteins, their role in PI3K/AKT signaling, and their influence on vemurafenib-resistant melanoma cell characteristics.

摘要

尽管在治疗黑色素瘤方面取得了重大进展，但大多数患者仍会产生耐药性，其机制仍不完全清楚。因此，我们生成并鉴定了两种获得性耐药黑色素瘤细胞系，原发性 WM793B 和转移性 A375M，对 RAF 抑制剂 vemurafenib 产生耐药性。耐药性原发性 WM793B 黑色素瘤细胞的形态表现出 EMT 样特征，并表现出既有上皮特征又有间充质特征的混合表型。令人惊讶的是，vemurafenib 耐药黑色素瘤细胞的迁移能力降低，但也表现出集体迁移的趋势。信号通路分析显示，MAPK 重新激活和 PI3K/AKT 通路的激活取决于 vemurafenib 耐药细胞系。原发性 WM793B 黑色素瘤细胞对 vemurafenib 的获得性耐药导致对化疗的耐药。此外，细胞周期分析和细胞周期调节剂水平的改变表明，耐药细胞可能暂时在 G0/G1 期进入细胞周期阻滞，并获得慢周期细胞特征。在 WM793B 耐药性原发性黑色素瘤中发现 NME1 和 NME2 转移抑制蛋白水平降低，这可能是 vemurafenib 获得性耐药的结果，也是 PI3K/AKT 信号增强的原因之一。需要进一步研究以揭示 NME 蛋白的 vemurafenib 依赖性负调节剂、它们在 PI3K/AKT 信号中的作用以及它们对 vemurafenib 耐药黑色素瘤细胞特征的影响。

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