【佳學基因檢測】抑制 ERK 二聚化可改善 BRAF 驅動的甲狀腺未分化癌

品牌基因檢測怎么樣排隊

分析明白《Cell Mol Life Sci》在.?2022 Sep 3;79(9):504.發(fā)表了一篇題目為《抑制 ERK 二聚化可改善 BRAF 驅動的甲狀腺未分化癌》腫瘤靶向藥物治療基因檢測臨床研究文章。該研究由Miguel A Zaballos?#,?Adrián Acu?a-Ruiz?#,?Marta Morante,?Garcilaso Riesco-Eizaguirre,?Piero Crespo,?Pilar Santisteban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)容關鍵詞：

布拉夫,德爾-22379, ERK 二聚化, RAS,甲狀腺癌

腫瘤靶向治療基因檢測臨床應用結果

背景：RAS-to-ERK 信號傳導對晚期甲狀腺癌的發(fā)病和進展至關重要，阻斷 ERK 二聚化可在幾種人類癌癥中提供治療益處。在這里，我們分析了 DEL-22379（一種相對特異性的 ERK 二聚化抑制劑）對 RAS-to-ERK 信號級聯(lián)的激活以及體外和體內(nèi)腫瘤相關過程的影響。方法：我們使用了一組四人具有 BRAF 或 RAS 突變的間變性甲狀腺癌 (ATC) 細胞系以分析 ERK 動力學和腫瘤特異性特征。我們還使用 RNA 測序評估了 DEL-22379 對 ATC 細胞系轉錄景觀的影響，并評估了其在 ATC 原位小鼠模型中的治療效果。結果：DEL-22379 損害了 BRAF 中的上游 ERK 活化，但不損害 RAS-突變細胞。 DEL-22379 治療減弱了細胞活力和轉移相關過程，但主要在 BRAF 突變細胞中，而 BRAF 突變細胞的體內(nèi)腫瘤生長和傳播顯著降低，而 RAS 突變細胞則輕度降低。轉錄組學分析表明，DEL-22379 以相反的方向調(diào)節(jié) BRAF 和 RAS 突變細胞的轉錄景觀。結論：我們的研究結果表明，BRAF 和 RAS 突變的甲狀腺細胞對 DEL-22379 的反應不同，這不能用先前描述的抑制劑的作用機制。盡管如此，DEL-22379 在體內(nèi)表現(xiàn)出對 BRAF 突變細胞的顯著抗腫瘤作用，且明顯缺乏毒性，使其成為開發(fā)組合治療的有趣候選者。我們的數(shù)據(jù)強調(diào)了甲狀腺癌發(fā)病和進展的特定驅動突變引起的差異，在實驗和臨床方法中應考慮這一點。德爾-22379； ERK 二聚化； RAS；甲狀腺癌。

腫瘤發(fā)生與反復轉移國際數(shù)據(jù)庫描述：

Background:?RAS-to-ERK signaling is crucial for the onset and progression of advanced thyroid carcinoma, and blocking ERK dimerization provides a therapeutic benefit in several human carcinomas. Here we analyzed the effects of DEL-22379, a relatively specific ERK dimerization inhibitor, on the activation of the RAS-to-ERK signaling cascade and on tumor-related processes in vitro and in vivo.Methods:?We used a panel of four human anaplastic thyroid carcinoma (ATC) cell lines harboring BRAF or RAS mutations to analyze ERK dynamics and tumor-specific characteristics. We also assessed the impact of DEL-22379 on the transcriptional landscape of ATC cell lines using RNA-sequencing and evaluated its therapeutic efficacy in an orthotopic mouse model of ATC.Results:?DEL-22379 impaired upstream ERK activation in BRAF- but not RAS-mutant cells. Cell viability and metastasis-related processes were attenuated by DEL-22379 treatment, but mostly in BRAF-mutant cells, whereas in vivo tumor growth and dissemination were strongly reduced for BRAF-mutant cells and mildly reduced for RAS-mutant cells. Transcriptomics analyses indicated that DEL-22379 modulated the transcriptional landscape of BRAF- and RAS-mutant cells in opposite directions.Conclusions:?Our findings establish that BRAF- and RAS-mutant thyroid cells respond differentially to DEL-22379, which cannot be explained by the previously described mechanism of action of the inhibitor. Nonetheless, DEL-22379 demonstrated significant anti-tumor effects against BRAF-mutant cells in vivo with an apparent lack of toxicity, making it an interesting candidate for the development of combinatorial treatments. Our data underscore the differences elicited by the specific driver mutation for thyroid cancer onset and progression, which should be considered for experimental and clinical approaches.Keywords:?BRAF; DEL-22379; ERK dimerization; RAS; Thyroid cancer.