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

品牌基因檢測聯(lián)系方式—客觀性

開題評估《腫瘤突變基因檢測與個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。促進了腫瘤的正確治療與個性化用藥的發(fā)展，進一步強調(diào)了基因信息檢測與分析的重要性。

腫瘤靶向藥物及正確治療臨床研究內(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,信號通路,慢循環(huán)細胞,威羅非尼

腫瘤靶向治療基因檢測臨床應(yīng)用結(jié)果

盡管黑色素瘤的治療有顯著改善，但大多數(shù)患者會產(chǎn)生耐藥性，其機制仍未有效了解。因此，我們生成并表征了兩種黑色素瘤衍生細胞系，原發(fā)性 WM793B 和轉(zhuǎn)移性 A375M，對 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胞表現(xiàn)出遷移能力下降，但也表現(xiàn)出集體遷移的趨勢。信號通路分析揭示了 MAPK 的重新激活和 PI3K/AKT 通路的激活取決于威羅非尼耐藥細胞系。對威羅非尼的獲得性耐藥導致原發(fā)性 WM793B 黑色素瘤細胞對化療產(chǎn)生耐藥性。此外，細胞周期分析和細胞周期調(diào)節(jié)劑水平的改變表明，抗性細胞可能會在 G0/G1 期短暫進入細胞周期停滯并獲得慢周期細胞特征。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 信號增加的原因之一。需要進一步的研究來揭示 NME 蛋白的威羅非尼依賴性負調(diào)節(jié)因子、它們在 PI3K/AKT 信號傳導中的作用以及它們對威羅非尼耐藥黑色素瘤細胞特征的影響。耐藥性;上皮間質(zhì)轉(zhuǎn)化（EMT）；黑色素瘤;信號通路；慢循環(huán)細胞；威羅非尼。

腫瘤發(fā)生與反復(fù)轉(zhuǎn)移國際數(shù)據(jù)庫描述：

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.