https://www.yiliao.com/index.php?action=history&feed=atom&title=%E6%BF%80%E9%85%B6%E8%9E%8D%E5%90%88
激酶融合 - 版本历史
2026-04-18T17:14:35Z
本wiki的该页面的版本历史
MediaWiki 1.35.1
https://www.yiliao.com/index.php?title=%E6%BF%80%E9%85%B6%E8%9E%8D%E5%90%88&diff=313635&oldid=prev
77921020：建立内容为“<div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff…”的新页面
2026-01-07T11:37:12Z
<p>建立内容为“<div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff…”的新页面</p>
<p><b>新页面</b></p><div><div style="padding: 0 4%; line-height: 1.8; color: #1e293b; font-family: 'Helvetica Neue', Helvetica, 'PingFang SC', Arial, sans-serif; background-color: #ffffff; max-width: 1200px; margin: auto;"><br />
<br />
<div style="margin-bottom: 30px; border-bottom: 2.2px solid #0f172a; padding-bottom: 25px;"><br />
<p style="font-size: 1.1em; margin: 10px 0; color: #334155; text-align: justify;"><br />
<strong>[[激酶融合]] (Kinase Fusion)</strong> 是一种由于染色体易位、倒位或缺失导致的基因组结构变异，致使激酶基因（通常是保留激酶结构域的 3' 端）与另一个伴侣基因（通常是 5' 端）发生融合。这种融合通常会移除激酶原本的<strong>[[自抑制结构域]]</strong>，并通过伴侣基因介导的二聚化，导致激酶在无配体结合的情况下发生<strong>[[组成性激活]]</strong>。激酶融合是多种恶性肿瘤的强力驱动因素，包括 <strong>[[ALK]]</strong>、<strong>[[ROS1]]</strong>、<strong>[[RET]]</strong> 及 <strong>[[NTRK]]</strong> 等。针对此类变异的<strong>[[酪氨酸激酶抑制剂]] (TKI)</strong> 治疗效果显著，常被称为“钻石突变”。<br />
</p><br />
</div><br />
<br />
<div class="medical-infobox mw-collapsible mw-collapsed" style="width: 320px; float: right; margin: 0 0 25px 25px; border: 1.2px solid #bae6fd; border-radius: 12px; background-color: #ffffff; box-shadow: 0 8px 20px rgba(0,0,0,0.05); overflow: hidden;"><br />
<br />
<div style="padding: 15px; color: #1e40af; background: linear-gradient(135deg, #e0f2fe 0%, #bae6fd 100%); text-align: center; cursor: pointer;"><br />
<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">激酶融合</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">Oncogenic Gene Rearrangement · 点击展开</div><br />
</div><br />
<br />
<div class="mw-collapsible-content"><br />
<div style="padding: 25px; text-align: center; background-color: #f8fafc;"><br />
<div style="display: inline-block; background: #ffffff; border: 1px solid #e2e8f0; border-radius: 12px; padding: 20px; box-shadow: 0 4px 10px rgba(0,0,0,0.04);"><br />
<br />
</div><br />
<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">核心结果：嵌合蛋白 (Chimeric Protein)</div><br />
</div><br />
<br />
<table style="width: 100%; border-spacing: 0; border-collapse: collapse; font-size: 0.82em;"><br />
<tr style="background-color: #f8fafc;"><th colspan="2" style="padding: 5px; color: #1e40af; border-bottom: 1px solid #e2e8f0;">变异特征</th></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">变异类型</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">结构变异 (SV) / 重排</td></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">功能后果</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">组成性激酶活性激活</td></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">检测金标准</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">[[RNA-seq]] / [[NGS]]</td></tr><br />
<br />
<tr style="background-color: #f8fafc;"><th colspan="2" style="padding: 5px; color: #1e40af; border-bottom: 1px solid #e2e8f0; border-top: 1px solid #e2e8f0;">经典靶点</th></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">肺癌双星</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">[[ALK]], [[ROS1]]</td></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">泛癌种</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">[[NTRK1/2/3]], [[RET]]</td></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">消化道/尿路</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">[[FGFR2]], [[FGFR3]]</td></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; color: #475569;">治疗手段</th><td style="padding: 6px 10px; color: #059669;">ATP 竞争性 TKI</td></tr><br />
</table><br />
</div><br />
</div><br />
<br />
<h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">分子机制：失控的信号发生器</h2><br />
<br />
<p style="margin: 15px 0; text-align: justify;"><br />
激酶融合导致肿瘤发生的机制高度一致，主要包含以下三个核心要素：<br />
</p><br />
<ul style="padding-left: 25px; color: #334155;"><br />
<li style="margin-bottom: 12px;"><strong>启动子置换 (Promoter Swapping)：</strong> 激酶基因的 3' 端（编码激酶结构域）连接到了一个高表达伴侣基因的启动子下游，导致激酶蛋白在肿瘤细胞中<strong>异常高表达</strong>。</li><br />
<li style="margin-bottom: 12px;"><strong>自抑制丢失 (Loss of Auto-inhibition)：</strong> 正常的受体酪氨酸激酶（RTK）在未结合配体时，通过胞外域或近膜域维持非活性构象。融合通常会切除这些负调控区域，使激酶处于“裸露”状态。</li><br />
<li style="margin-bottom: 12px;"><strong>强制二聚化 (Constitutive Dimerization)：</strong> 5' 端的伴侣基因（如 EML4, KIF5B, ETV6）通常含有<strong>[[卷曲螺旋]] (Coiled-coil)</strong> 或其他二聚化模体。这迫使融合蛋白在没有配体的情况下发生二聚化和交叉磷酸化，从而持续激活下游 [[MAPK]]、[[PI3K]] 和 [[JAK/STAT]] 通路。</li><br />
</ul><br />
<br />
<h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">核心融合靶点与药物矩阵</h2><br />
<div style="overflow-x: auto; margin: 30px auto;"><br />
<table style="width: 100%; border-collapse: collapse; border: 1.2px solid #cbd5e1; font-size: 0.95em; text-align: left;"><br />
<tr style="background-color: #f8fafc; border-bottom: 2px solid #0f172a;"><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a;">融合基因 (3'端)</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">常见伴侣 (5'端)</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">当前标准治疗 (SOC)</th><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[ALK]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">EML4 (NSCLC)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">[[阿来替尼]] (一线), [[洛拉替尼]] (三代)</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[ROS1]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">CD74, EZR, SDC4</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">[[瑞波替尼]] (Repotrectinib), [[Taletrectinib]]</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[RET]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">KIF5B (NSCLC), CCDC6 (甲状腺)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">[[塞尔帕替尼]] (Selpercatinib), [[普拉替尼]]</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[NTRK]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">ETV6, LMNA (泛癌种)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">[[拉罗替尼]] (Larotrectinib), [[恩曲替尼]]</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[FGFR2]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">BICC1 (胆管癌)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">[[佩米替尼]] (Pemigatinib), [[福替尼]]</td><br />
</tr><br />
</table><br />
</div><br />
<br />
<h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">诊断与治疗挑战</h2><br />
<ul style="padding-left: 25px; color: #334155;"><br />
<li style="margin-bottom: 12px;"><strong>检测方法的选择：</strong><br />
<ul style="margin-top: 5px; list-style-type: circle;"><br />
<li><strong>DNA-NGS：</strong> 常规手段，但对于内含子极长（如 NTRK2/3）的基因容易出现<strong>漏检</strong>。</li><br />
<li><strong>RNA-NGS：</strong> 检测融合转录本，是诊断激酶融合的<strong>金标准</strong>，能发现 DNA 层面难以覆盖的剪接变异。</li><br />
<li><strong>IHC：</strong> 仅作为 ALK/ROS1 的初筛工具，对 NTRK 假阳性率较高。</li><br />
</ul><br />
</li><br />
<li style="margin-bottom: 12px;"><strong>耐药机制：</strong> 长期 TKI 治疗必然导致耐药。主要机制包括：<br />
<ul style="margin-top: 5px; list-style-type: circle;"><br />
<li><strong>溶剂前沿突变 (Solvent Front Mutations)：</strong> 如 ALK G1202R, ROS1 G2032R，阻碍药物结合。需要下一代大环分子药物（如 Lorlatinib, Repotrectinib）克服。</li><br />
<li><strong>旁路激活：</strong> 如 MET 扩增、KRAS 突变等。</li><br />
</ul><br />
</li><br />
</ul><br />
<br />
<h2 style="background: #f1f5f9; color: #0f172a; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #0f172a; font-weight: bold;">关键相关概念</h2><br />
<div style="background-color: #f8fafc; border: 1px solid #e2e8f0; border-radius: 8px; padding: 15px; margin: 20px 0;"><br />
<p style="margin: 0; color: #334155; line-height: 2;"><br />
[[染色体易位]] • [[不限癌种疗法 (Tissue-Agnostic)]] • [[RNA-seq]] • [[看门人突变]] • [[溶剂前沿区]]<br />
</p><br />
</div><br />
<br />
<div style="font-size: 0.92em; line-height: 1.6; color: #1e293b; margin-top: 50px; border-top: 2.5px solid #0f172a; padding: 15px 25px; background-color: #f8fafc; border-radius: 0 0 10px 10px;"><br />
<span style="color: #0f172a; font-weight: bold; font-size: 1.05em; display: inline-block; margin-bottom: 15px;">学术参考文献 [Academic Review & Verified]</span><br />
<br />
<p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;"><br />
[1] <strong>Shaw AT, et al. (2013).</strong> <em>Crizotinib in ROS1-rearranged non-small-cell lung cancer.</em> <strong>[[The New England Journal of Medicine]]</strong>. 371(21):1963-1971.<br><br />
<span style="color: #475569;">[经典文献]：确立了 ROS1 融合作为肺癌独立治疗靶点的地位，并验证了激酶抑制剂的高效性。</span><br />
</p><br />
<br />
<p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;"><br />
[2] <strong>Drilon A, et al. (2018).</strong> <em>Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children.</em> <strong>[[The New England Journal of Medicine]]</strong>. 378(8):731-739.<br><br />
<span style="color: #475569;">[里程碑]：开启了“不限癌种”治疗时代，证明了只要有 NTRK 融合，无论何种肿瘤，TKI 均能产生深度缓解。</span><br />
</p><br />
<br />
<p style="margin: 12px 0;"><br />
[3] <strong>Stransky N, Cerami E, Schalm S, et al. (2014).</strong> <em>The landscape of kinase fusions in cancer.</em> <strong>[[Nature Communications]]</strong>. 5:4846.<br><br />
<span style="color: #475569;">[全景综述]：通过大规模基因组学分析，系统描绘了人类癌症中激酶融合的分布图谱和伴侣基因特征。</span><br />
</p><br />
</div><br />
<br />
<div style="margin: 40px 0; border: 1.5px solid #0f172a; border-radius: 8px; overflow: hidden; font-size: 0.9em;"><br />
<div style="background-color: #0f172a; color: #ffffff; text-align: center; font-weight: bold; padding: 10px; letter-spacing: 1px;">激酶融合 · 知识图谱导航</div><br />
<table style="width: 100%; border-collapse: collapse; background-color: #ffffff;"><br />
<tr style="border-bottom: 1px solid #f1f5f9;"><br />
<td style="width: 95px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">热门靶点</td><br />
<td style="padding: 10px 15px; color: #334155;">[[ALK]] • [[ROS1]] • [[RET]] • [[NTRK]] • [[FGFR2]]</td><br />
</tr><br />
<tr style="border-bottom: 1px solid #f1f5f9;"><br />
<td style="width: 95px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">检测技术</td><br />
<td style="padding: 10px 15px; color: #334155;">[[RNA-seq]] • [[FISH]] • [[DNA-NGS]]</td><br />
</tr><br />
<tr><br />
<td style="width: 95px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">耐药机理</td><br />
<td style="padding: 10px 15px; color: #334155;">[[溶剂前沿突变]] • [[看门人突变]] • [[旁路激活]]</td><br />
</tr><br />
</table><br />
</div><br />
<br />
</div></div>
77921020