【佳學(xué)基因檢測(cè)】抑制 ERK 二聚化可改善 BRAF 驅(qū)動(dòng)的甲狀腺未分化癌

品牌基因檢測(cè)怎么樣排隊(duì)

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(qū)動(dòng)的甲狀腺未分化癌》腫瘤靶向藥物治療基因檢測(cè)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(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：

布拉夫,德?tīng)?22379, ERK 二聚化, RAS,甲狀腺癌

腫瘤靶向治療基因檢測(cè)臨床應(yīng)用結(jié)果

背景：RAS-to-ERK 信號(hào)傳導(dǎo)對(duì)晚期甲狀腺癌的發(fā)病和進(jìn)展至關(guān)重要，阻斷 ERK 二聚化可在幾種人類(lèi)癌癥中提供治療益處。在這里，我們分析了 DEL-22379（一種相對(duì)特異性的 ERK 二聚化抑制劑）對(duì) RAS-to-ERK 信號(hào)級(jí)聯(lián)的激活以及體外和體內(nèi)腫瘤相關(guān)過(guò)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(xì)胞系以分析 ERK 動(dòng)力學(xué)和腫瘤特異性特征。我們還使用 RNA 測(cè)序評(píng)估了 DEL-22379 對(duì) ATC 細(xì)胞系轉(zhuǎn)錄景觀(guān)的影響，并評(píng)估了其在 ATC 原位小鼠模型中的治療效果。結(jié)果：DEL-22379 損害了 BRAF 中的上游 ERK 活化，但不損害 RAS-突變細(xì)胞。 DEL-22379 治療減弱了細(xì)胞活力和轉(zhuǎn)移相關(guān)過(guò)程，但主要在 BRAF 突變細(xì)胞中，而 BRAF 突變細(xì)胞的體內(nèi)腫瘤生長(zhǎng)和傳播顯著降低，而 RAS 突變細(xì)胞則輕度降低。轉(zhuǎn)錄組學(xué)分析表明，DEL-22379 以相反的方向調(diào)節(jié) BRAF 和 RAS 突變細(xì)胞的轉(zhuǎn)錄景觀(guān)。結(jié)論：我們的研究結(jié)果表明，BRAF 和 RAS 突變的甲狀腺細(xì)胞對(duì) DEL-22379 的反應(yīng)不同，這不能用先前描述的抑制劑的作用機(jī)制。盡管如此，DEL-22379 在體內(nèi)表現(xiàn)出對(duì) BRAF 突變細(xì)胞的顯著抗腫瘤作用，且明顯缺乏毒性，使其成為開(kāi)發(fā)組合治療的有趣候選者。我們的數(shù)據(jù)強(qiáng)調(diào)了甲狀腺癌發(fā)病和進(jìn)展的特定驅(qū)動(dòng)突變引起的差異，在實(shí)驗(yàn)和臨床方法中應(yīng)考慮這一點(diǎn)。德?tīng)?22379； ERK 二聚化； RAS；甲狀腺癌。

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