【佳學(xué)基因檢測(cè)】Vemurafenib 耐藥黑色素瘤細(xì)胞系的表征揭示了靶向治療耐藥的新特征

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開題評(píng)估《腫瘤突變基因檢測(cè)與個(gè)性化治療方案的制定》《Int J Mol Sci》在.?2022 Aug 31;23(17):9910.發(fā)表了一篇題目為《Vemurafenib 耐藥黑色素瘤細(xì)胞系的表征揭示了靶向治療耐藥的新特征》腫瘤靶向藥物治療基因檢測(cè)臨床研究文章。該研究由Martina Radi?,?Ignacija Vla?i?,?Maja Jazvin??ak Jembrek,?An?ela Horvat,?Ana Tadijan,?Maja Sabol,?Marko Du?evi?,?Maja Herak Bosnar,?Neda Slade?等完成。促進(jìn)了腫瘤的正確治療與個(gè)性化用藥的發(fā)展，進(jìn)一步強(qiáng)調(diào)了基因信息檢測(cè)與分析的重要性。

腫瘤靶向藥物及正確治療臨床研究?jī)?nèi)容關(guān)鍵詞：

NME 轉(zhuǎn)移抑制蛋白,耐藥性,上皮間質(zhì)轉(zhuǎn)化（EMT）,黑色素瘤,信號(hào)通路,慢循環(huán)細(xì)胞,威羅非尼

腫瘤靶向治療基因檢測(cè)臨床應(yīng)用結(jié)果

盡管黑色素瘤的治療有顯著改善，但大多數(shù)患者會(huì)產(chǎn)生耐藥性，其機(jī)制仍未有效了解。因此，我們生成并表征了兩種黑色素瘤衍生細(xì)胞系，原發(fā)性 WM793B 和轉(zhuǎn)移性 A375M，對(duì) RAF 抑制劑威羅非尼具有獲得性耐藥性。耐藥原發(fā)性 WM793B 黑色素瘤細(xì)胞的形態(tài)表現(xiàn)出 EMT 樣特征，并表現(xiàn)出具有上皮和間充質(zhì)特征的混合表型。令人驚訝的是，威羅菲尼耐藥的黑色素瘤細(xì)胞表現(xiàn)出遷移能力下降，但也表現(xiàn)出集體遷移的趨勢(shì)。信號(hào)通路分析揭示了 MAPK 的重新激活和 PI3K/AKT 通路的激活取決于威羅非尼耐藥細(xì)胞系。對(duì)威羅非尼的獲得性耐藥導(dǎo)致原發(fā)性 WM793B 黑色素瘤細(xì)胞對(duì)化療產(chǎn)生耐藥性。此外，細(xì)胞周期分析和細(xì)胞周期調(diào)節(jié)劑水平的改變表明，抗性細(xì)胞可能會(huì)在 G0/G1 期短暫進(jìn)入細(xì)胞周期停滯并獲得慢周期細(xì)胞特征。在 WM793B 耐藥的原發(fā)性黑色素瘤中發(fā)現(xiàn) NME1 和 NME2 轉(zhuǎn)移抑制蛋白水平降低，這可能是威羅非尼獲得性耐藥的結(jié)果，也是 PI3K/AKT 信號(hào)增加的原因之一。需要進(jìn)一步的研究來揭示 NME 蛋白的威羅非尼依賴性負(fù)調(diào)節(jié)因子、它們?cè)?PI3K/AKT 信號(hào)傳導(dǎo)中的作用以及它們對(duì)威羅非尼耐藥黑色素瘤細(xì)胞特征的影響。耐藥性;上皮間質(zhì)轉(zhuǎn)化（EMT）；黑色素瘤;信號(hào)通路；慢循環(huán)細(xì)胞；威羅非尼。

腫瘤發(fā)生與反復(fù)轉(zhuǎn)移國(guó)際數(shù)據(jù)庫(kù)描述：

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.Keywords:?NME metastasis suppressor proteins; drug resistance; epithelial–mesenchymal transition (EMT); melanoma; signaling pathways; slow-cycling cells; vemurafenib.