【佳學(xué)基因檢測】基因檢測 MPNST 的重要驅(qū)動(dòng)因子RABL6A ，通過負(fù)向調(diào)節(jié) RB1 通路增強(qiáng)腫瘤細(xì)胞對 CDK4/6靶向藥物的敏感性

基因變異引起的癌癥原理

學(xué)習(xí)腫瘤基因檢測全面性的標(biāo)準(zhǔn)與實(shí)施方案記錄《Clin Cancer Res》在. 2020 Jun 15;26(12):2997-3011.發(fā)表了一篇題目為《基因檢測 MPNST 的重要驅(qū)動(dòng)因子RABL6A ，通過負(fù)向調(diào)節(jié) RB1 通路增強(qiáng)腫瘤細(xì)胞對 CDK4/6靶向藥物的敏感性》腫瘤靶向藥物治療基因檢測臨床研究文章。該研究由Jordan L Kohlmeyer  , Courtney A Kaemmer , Casey Pulliam , Chandra K Maharjan , Allison Moreno Samayoa , Heather J Major , Kendall E Cornick , Vickie Knepper-Adrian , Rajesh Khanna , Jessica C Sieren , Mariah R Leidinger , David K Meyerholz , K D Zamba , Jill M Weimer , Rebecca D Dodd  , Benjamin W Darbro , Munir R Tanas , Dawn E Quelle   等完成。促進(jìn)了惡性外周神經(jīng)鞘瘤的致病基因鑒定和轉(zhuǎn)移風(fēng)險(xiǎn)評估的正確性，使得神經(jīng)科也可以采用美國制裁的技術(shù)進(jìn)行正確診斷與個(gè)性化治療。

腫瘤大數(shù)據(jù)臨床研究內(nèi)容關(guān)鍵詞：

基因檢測,MPNST,驅(qū)動(dòng)因子,RABL6A,負(fù)向調(diào)節(jié), RB1通路,靶向藥物,敏感性，神經(jīng)科

腫瘤靶向治療基因檢測臨床應(yīng)用結(jié)果

目的：惡性外周神經(jīng)鞘瘤（MPNST）是一種致命的肉瘤，缺乏有效的治療方法。在大多數(shù) MPNST 中，視網(wǎng)膜母細(xì)胞瘤 (RB1) 腫瘤抑制因子會因細(xì)胞周期蛋白依賴性激酶 (CDK) 的過度激活而失效，通常是由于諸如 p27(Kip1) 等 CDK 抑制蛋白的丟失。 RABL6A 是 RB1 的抑制劑，其在 MPNSTs 中的作用尚不清楚。為了深入了解 MPNST 的發(fā)展并建立新的治療方案，我們研究了 MPNST 中的 RABL6A-RB1 信號傳導(dǎo)和基于 CDK 抑制劑的治療。實(shí)驗(yàn)設(shè)計(jì)：我們通過 RNA 測序 (RNA-Seq) 和 IHC 檢查了患者匹配的 MPNST 和前體病變。確定了在 MPNST 系和正常人雪旺細(xì)胞中沉默 RABL6A 和/或 p27 的分子和生物學(xué)效應(yīng)。在 MPNST 細(xì)胞和原位腫瘤中測量了 CDK 抑制劑的腫瘤抑制作用。結(jié)果：與前體病變相比，RABL6A 在人類 MPNST 中顯著上調(diào)，與 p27 水平呈負(fù)相關(guān)。沉默 RABL6A 導(dǎo)致 MPNST 細(xì)胞死亡和 G1 期停滯，這與 p27 上調(diào)、CDK 下調(diào)和 RB1 激活同時(shí)發(fā)生。 RABL6A 缺失的生長抑制作用及其對 RB1 的調(diào)節(jié)在很大程度上通過 p27 耗竭得以挽救。重要的是，使用 CDK4/6 抑制劑 (palbociclib) 重新激活 RB1 在體外以 RABL6A 依賴性方式殺死 MPNST 細(xì)胞并抑制體內(nèi) MPNST 生長。靶向多種 RB1 激酶（CDK4/6、CDK2）的低劑量藥物組合具有增強(qiáng)的抗腫瘤活性，與潛在的 MPNST 細(xì)胞再分化相關(guān)。結(jié)論：RABL6A 是 MPNST 發(fā)病機(jī)制的新驅(qū)動(dòng)因素，部分通過 p27-RB1 失活起作用。我們的結(jié)果表明 RB1 靶向治療與多途徑藥物可能有效治療 MPNST。

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

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are deadly sarcomas that lack effective therapies. In most MPNSTs, the retinoblastoma (RB1) tumor suppressor is disabled by hyperactivation of cyclin-dependent kinases (CDK), commonly through loss of CDK-inhibitory proteins such as p27(Kip1). RABL6A is an inhibitor of RB1 whose role in MPNSTs is unknown. To gain insight into MPNST development and establish new treatment options, we investigated RABL6A-RB1 signaling and CDK inhibitor-based therapy in MPNSTs.Experimental design: We examined patient-matched MPNSTs and precursor lesions by RNA sequencing (RNA-Seq) and IHC. Molecular and biological effects of silencing RABL6A and/or p27 in MPNST lines and normal human Schwann cells were determined. Tumor-suppressive effects of CDK inhibitors were measured in MPNST cells and orthotopic tumors.Results: RABL6A was dramatically upregulated in human MPNSTs compared with precursor lesions, which correlated inversely with p27 levels. Silencing RABL6A caused MPNST cell death and G1 arrest that coincided with p27 upregulation, CDK downregulation, and RB1 activation. The growth-suppressive effects of RABL6A loss, and its regulation of RB1, were largely rescued by p27 depletion. Importantly, reactivation of RB1 using a CDK4/6 inhibitor (palbociclib) killed MPNST cells in vitro in an RABL6A-dependent manner and suppressed MPNST growth in vivo. Low-dose combination of drugs targeting multiple RB1 kinases (CDK4/6, CDK2) had enhanced antitumorigenic activity associated with potential MPNST cell redifferentiation.Conclusions: RABL6A is a new driver of MPNST pathogenesis that acts in part through p27-RB1 inactivation. Our results suggest RB1 targeted therapy with multiple pathway drugs may effectively treat MPNSTs.