https://www.yiliao.com/index.php?action=history&feed=atom&title=MAPK%2FERK_%E9%80%9A%E8%B7%AF
MAPK/ERK 通路 - 版本历史
2026-04-18T17:28:26Z
本wiki的该页面的版本历史
MediaWiki 1.35.1
https://www.yiliao.com/index.php?title=MAPK/ERK_%E9%80%9A%E8%B7%AF&diff=313618&oldid=prev
2026年1月7日 (三) 08:55 77921020
2026-01-07T08:55:53Z
<p></p>
<table class="diff diff-contentalign-left diff-editfont-monospace" data-mw="interface">
<col class="diff-marker" />
<col class="diff-content" />
<col class="diff-marker" />
<col class="diff-content" />
<tr class="diff-title" lang="zh-Hans-CN">
<td colspan="2" style="background-color: #fff; color: #202122; text-align: center;">←上一版本</td>
<td colspan="2" style="background-color: #fff; color: #202122; text-align: center;">2026年1月7日 (三) 08:55的版本</td>
</tr><tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l7" >第7行：</td>
<td colspan="2" class="diff-lineno">第7行：</td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <div class="medical-infobox mw-collapsible" 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;"></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <div class="medical-infobox mw-collapsible <ins class="diffchange diffchange-inline">mw-collapsed</ins>" 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;"></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <div style="padding: 15px; color: #1e40af; background: linear-gradient(135deg, #e0f2fe 0%, #bae6fd 100%); text-align: center; cursor: pointer;"></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <div style="padding: 15px; color: #1e40af; background: linear-gradient(135deg, #e0f2fe 0%, #bae6fd 100%); text-align: center; cursor: pointer;"></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">MAPK/ERK 通路</div></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">MAPK/ERK 通路</div></div></td></tr>
<tr><td class='diff-marker'>−</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #ffe49c; vertical-align: top; white-space: pre-wrap;"><div> <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">Signal Transduction Cascade · <del class="diffchange diffchange-inline">档案</del></div></div></td><td class='diff-marker'>+</td><td style="color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #a3d3ff; vertical-align: top; white-space: pre-wrap;"><div> <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">Signal Transduction Cascade · <ins class="diffchange diffchange-inline">点击展开</ins></div></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></div></td></tr>
<tr><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></td><td class='diff-marker'> </td><td style="background-color: #f8f9fa; color: #202122; font-size: 88%; border-style: solid; border-width: 1px 1px 1px 4px; border-radius: 0.33em; border-color: #eaecf0; vertical-align: top; white-space: pre-wrap;"><div> </div></td></tr>
</table>
77921020
https://www.yiliao.com/index.php?title=MAPK/ERK_%E9%80%9A%E8%B7%AF&diff=313617&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
2026-01-07T08:53:58Z
<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>[[RAS-RAF-MEK-ERK 通路]]</strong>，也称为 <strong>[[MAPK/ERK 通路]]</strong>，是真核细胞中最重要的信号转导级联之一。该通路将细胞表面的生长因子信号（如 [[EGFR]]、[[HER2]]）传递至细胞核，调控基因转录、细胞增殖、分化及存活。在肿瘤学中，该通路的异常激活（主要由 <strong>[[KRAS]]</strong>、<strong>[[BRAF]]</strong> 突变驱动）存在于超过 30% 的人类恶性肿瘤中。2026 年的治疗范式已从单纯的激酶抑制，演进为涵盖 <strong>[[Pan-KRAS 抑制剂]]</strong>、<strong>[[二聚体阻断]]</strong> 及 <strong>[[垂直封锁]]</strong> 的立体攻坚战。<br />
</p><br />
</div><br />
<br />
<div class="medical-infobox mw-collapsible" 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;">MAPK/ERK 通路</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">Signal Transduction Cascade · 档案</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;">核心逻辑：三级激酶级联放大</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;">核心组件</th></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">GTPase 开关</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">[[KRAS]], [[NRAS]], [[HRAS]]</td></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">MAP3K (上游)</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">[[ARAF]], [[BRAF]], [[CRAF]]</td></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">MAP2K (中游)</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">[[MEK1]], [[MEK2]]</td></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">MAPK (下游)</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">[[ERK1]], [[ERK2]]</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;">临床概貌 (2026)</th></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">主要突变瘤种</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">胰腺癌, 结直肠癌, 肺癌, 黑色素瘤</td></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; border-bottom: 1px dotted #e2e8f0; color: #475569;">最新突破</th><td style="padding: 6px 10px; border-bottom: 1px dotted #e2e8f0;">[[Pan-KRAS 抑制剂]]</td></tr><br />
<tr><th style="text-align: left; padding: 6px 10px; color: #475569;">耐药机制</th><td style="padding: 6px 10px; color: #b91c1c;">反馈激活, 旁路扩增</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;">级联机制：精密的分子接力</h2><br />
<br />
<p style="margin: 15px 0; text-align: justify;"><br />
该通路的激活是一个严格受控的线性过程，但在肿瘤中常陷入“永久开启”模式：<br />
</p><br />
<ol style="padding-left: 25px; color: #334155;"><br />
<li style="margin-bottom: 12px;"><strong>上游输入 (RTK → RAS)：</strong> 生长因子结合受体（如 [[EGFR]]）导致受体二聚化，通过接头蛋白 [[GRB2]] 和 [[SOS1]]，促使 <strong>[[RAS]]</strong> 蛋白从非活性的 GDP 结合态转换为活性的 <strong>[[GTP 结合态]]</strong>。</li><br />
<li style="margin-bottom: 12px;"><strong>膜募集与二聚化 (RAS → RAF)：</strong> 活化的 RAS-GTP 将 <strong>[[RAF]]</strong> 激酶募集至细胞膜。RAF 随后发生同源或异源二聚化（如 BRAF-CRAF 二聚体），这是 RAF 激活的关键步骤。</li><br />
<li style="margin-bottom: 12px;"><strong>双重磷酸化放大 (RAF → MEK → ERK)：</strong> 活化的 RAF 磷酸化 <strong>[[MEK1/2]]</strong> 的 Ser218/222；活化的 MEK 再双重磷酸化 <strong>[[ERK1/2]]</strong> 的 Thr202/Tyr204。信号在此过程中被逐级放大。</li><br />
<li style="margin-bottom: 12px;"><strong>效应执行 (ERK → 核)：</strong> 磷酸化的 ERK 入核，激活 [[c-Myc]]、[[Elk-1]] 等转录因子，启动细胞周期。</li><br />
</ol><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;">2026 变异图谱与治疗矩阵</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;">关键节点</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">主要突变形式</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">2026 靶向策略</th><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[KRAS]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">G12C, G12D, G12V</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">[[Adagrasib]] (G12C), [[Pan-KRAS 抑制剂]], 分子胶</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[BRAF]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">V600E (I类), 融合 (II类)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">[[双靶联用]] (I类), [[Pan-RAF 抑制剂]] (II类)</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[MEK1]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">P124L, E203K (耐药)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">[[变构抑制剂]] + [[ERK 抑制剂]]</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[NF1]]</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">功能缺失 (LoF)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">[[MEK 抑制剂]] (如司美替尼)</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;">挑战：耐药与反馈回路</h2><br />
<p style="margin: 15px 0; text-align: justify;"><br />
靶向该通路的最大挑战在于其极强的适应性可塑性：<br />
</p><br />
<ul style="padding-left: 25px; color: #334155;"><br />
<li style="margin-bottom: 12px;"><strong>反馈抑制解除：</strong> 正常情况下，ERK 会负反馈抑制上游 EGFR/SOS1。药物阻断 ERK 信号后，负反馈消失，导致 <strong>[[EGFR 反馈]]</strong> 激活，这是结直肠癌单药治疗无效的主因。</li><br />
<li style="margin-bottom: 12px;"><strong>矛盾激活 (Paradoxical Activation)：</strong> 第一代 BRAF 抑制剂结合单体 RAF 后，会诱导其构象改变并促进 RAF 二聚化，反而激活野生型细胞中的 MAPK 通路，导致继发性皮肤癌。</li><br />
<li style="margin-bottom: 12px;"><strong>解决方案：</strong> 2026 年标准已全面转向 <strong>[[垂直阻断]]</strong>（RAFi + MEKi）和 <strong>[[三联封锁]]</strong>（+ EGFRi/SHP2i）。</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 />
[[KRAS G12C]] • [[Pan-RAF 抑制剂]] • [[DUSP 磷酸酶]] • [[支架蛋白 (KSR)]] • [[垂直抑制策略]] • [[SHP2]]<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>Downward J. (2003).</strong> <em>Targeting RAS signalling pathways in cancer therapy.</em> <strong>[[Nature Reviews Cancer]]</strong>. 3(1):11-22.<br><br />
<span style="color: #475569;">[经典综述]：奠基性文献，详尽阐述了 RAS-RAF-MEK-ERK 的信号传递逻辑及早期靶向尝试的失败原因。</span><br />
</p><br />
<br />
<p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;"><br />
[2] <strong>Samatar AA, Poulikakos PI. (2014).</strong> <em>Targeting RAS–ERK signalling in cancer: promises and challenges.</em> <strong>[[Nature Reviews Drug Discovery]]</strong>. 13(12):928-942.<br><br />
<span style="color: #475569;">[机制解析]：深入剖析了“矛盾激活”和反馈回路的分子机制，为垂直阻断策略提供了理论支撑。</span><br />
</p><br />
<br />
<p style="margin: 12px 0;"><br />
[3] <strong>Canon J, et al. (2019/2026 Context).</strong> <em>The clinical development of KRAS G12C inhibitors.</em> <strong>[[Nature]]</strong>. 575:217–223.<br><br />
<span style="color: #475569;">[里程碑]：标志着 RAS 蛋白从“不可成药”迈向“可成药”时代的开山之作，引领了 2026 年 Pan-KRAS 药物的爆发。</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;">MAPK 通路 · 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;">核心节点</td><br />
<td style="padding: 10px 15px; color: #334155;">[[KRAS]] → [[BRAF]] → [[MEK1]] → [[ERK2]]</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;">治疗策略</td><br />
<td style="padding: 10px 15px; color: #334155;">[[三联封锁方案]] • [[垂直阻断]] • [[分子胶降解]]</td><br />
</tr><br />
<tr><br />
<td style="width: 95px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">关联通路</td><br />
<td style="padding: 10px 15px; color: #334155;">[[PI3K/Akt 通路]] • [[mTOR 通路]] • [[Wnt 通路]]</td><br />
</tr><br />
</table><br />
</div><br />
<br />
</div></div>
77921020