https://www.yiliao.com/index.php?action=history&feed=atom&title=ALK_%E6%BF%80%E9%85%B6%E7%BB%93%E6%9E%84%E5%9F%9F%E7%AA%81%E5%8F%98
ALK 激酶结构域突变 - 版本历史
2026-04-20T15:26:35Z
本wiki的该页面的版本历史
MediaWiki 1.35.1
https://www.yiliao.com/index.php?title=ALK_%E6%BF%80%E9%85%B6%E7%BB%93%E6%9E%84%E5%9F%9F%E7%AA%81%E5%8F%98&diff=315636&oldid=prev
2026年1月25日 (日) 01:30 77921020
2026-01-25T01:30:12Z
<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25日 (日) 01:30的版本</td>
</tr><tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l63" >第63行：</td>
<td colspan="2" class="diff-lineno">第63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 style="overflow-x: auto; margin: 30px auto; max-width: 95%;"></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="overflow-x: auto; margin: 30px auto; max-width: 95%;"></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> <table style="width: 100%; border-collapse: collapse; border: 1.2px solid #cbd5e1; font-size: 0.9em; text-align: center;"></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> <table style="width: 100%; border-collapse: collapse; border: 1.2px solid #cbd5e1; font-size: 0.9em; text-align: center;"></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> <tr style="background-color: #<del class="diffchange diffchange-inline">0f172a</del>; color: #<del class="diffchange diffchange-inline">ffffff</del>;"></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> <tr style="background-color: #<ins class="diffchange diffchange-inline">eff6ff</ins>; color: #<ins class="diffchange diffchange-inline">1e40af</ins>;"></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> <th style="padding: 12px; border: 1px solid #cbd5e1; width: 15%;">突变位点</th></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> <th style="padding: 12px; border: 1px solid #cbd5e1<ins class="diffchange diffchange-inline">; border-bottom: 2px solid #60a5fa</ins>; width: 15%;">突变位点</th></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> <th style="padding: 12px; border: 1px solid #cbd5e1; width: 25%;">一代<br><strong>[[克唑替尼]]</strong></th></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> <th style="padding: 12px; border: 1px solid #cbd5e1<ins class="diffchange diffchange-inline">; border-bottom: 2px solid #60a5fa</ins>; width: 25%;">一代<br><strong>[[克唑替尼]]</strong></th></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> <th style="padding: 12px; border: 1px solid #cbd5e1; width: 25%;">二代<br><strong>[[阿来]]</strong>/<strong>[[塞瑞]]</strong>/<strong>[[布格]]</strong></th></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> <th style="padding: 12px; border: 1px solid #cbd5e1<ins class="diffchange diffchange-inline">; border-bottom: 2px solid #60a5fa</ins>; width: 25%;">二代<br><strong>[[阿来]]</strong>/<strong>[[塞瑞]]</strong>/<strong>[[布格]]</strong></th></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> <th style="padding: 12px; border: 1px solid #cbd5e1; width: 35%;">三代<br><strong>[[洛拉替尼]]</strong></th></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> <th style="padding: 12px; border: 1px solid #cbd5e1<ins class="diffchange diffchange-inline">; border-bottom: 2px solid #60a5fa</ins>; width: 35%;">三代<br><strong>[[洛拉替尼]]</strong></th></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> </tr></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> </tr></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> <tr style="background-color: #<del class="diffchange diffchange-inline">f1f5f9</del>; font-weight: bold; text-align: left;"></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> <tr style="background-color: #<ins class="diffchange diffchange-inline">f8fafc</ins>; font-weight: bold; text-align: left;"></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> <td colspan="4" style="padding: 8px 12px; border: 1px solid #cbd5e1; color: #<del class="diffchange diffchange-inline">475569</del>;">I. 常见耐药突变 (Common)</td></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> <td colspan="4" style="padding: 8px 12px; border: 1px solid #cbd5e1; color: #<ins class="diffchange diffchange-inline">64748b</ins>;">I. 常见耐药突变 (Common)</td></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> </tr></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> </tr></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> <tr></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> <tr></div></td></tr>
<tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l90" >第90行：</td>
<td colspan="2" class="diff-lineno">第90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> <td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">高度敏感</td></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> <td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">高度敏感</td></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> </tr></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> </tr></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> <tr style="background-color: #<del class="diffchange diffchange-inline">f1f5f9</del>; font-weight: bold; text-align: left;"></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> <tr style="background-color: #<ins class="diffchange diffchange-inline">f8fafc</ins>; font-weight: bold; text-align: left;"></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> <td colspan="4" style="padding: 8px 12px; border: 1px solid #cbd5e1; color: #<del class="diffchange diffchange-inline">475569</del>;">II. 难治性突变 (Recalcitrant)</td></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> <td colspan="4" style="padding: 8px 12px; border: 1px solid #cbd5e1; color: #<ins class="diffchange diffchange-inline">64748b</ins>;">II. 难治性突变 (Recalcitrant)</td></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> </tr></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> </tr></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> <tr></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> <tr></div></td></tr>
<tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l111" >第111行：</td>
<td colspan="2" class="diff-lineno">第111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> <td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">敏感</td></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> <td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">敏感</td></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> </tr></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> </tr></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> <tr style="background-color: #<del class="diffchange diffchange-inline">f1f5f9</del>; font-weight: bold; text-align: left;"></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> <tr style="background-color: #<ins class="diffchange diffchange-inline">f8fafc</ins>; font-weight: bold; text-align: left;"></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> <td colspan="4" style="padding: 8px 12px; border: 1px solid #cbd5e1; color: #<del class="diffchange diffchange-inline">475569</del>;">III. 特殊突变 (Paradoxical)</td></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> <td colspan="4" style="padding: 8px 12px; border: 1px solid #cbd5e1; color: #<ins class="diffchange diffchange-inline">64748b</ins>;">III. 特殊突变 (Paradoxical)</td></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> </tr></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> </tr></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> <tr></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> <tr></div></td></tr>
</table>
77921020
https://www.yiliao.com/index.php?title=ALK_%E6%BF%80%E9%85%B6%E7%BB%93%E6%9E%84%E5%9F%9F%E7%AA%81%E5%8F%98&diff=315633&oldid=prev
2026年1月25日 (日) 01:19 77921020
2026-01-25T01:19:47Z
<p></p>
<a href="https://www.yiliao.com/index.php?title=ALK_%E6%BF%80%E9%85%B6%E7%BB%93%E6%9E%84%E5%9F%9F%E7%AA%81%E5%8F%98&diff=315633&oldid=315632">显示更改</a>
77921020
https://www.yiliao.com/index.php?title=ALK_%E6%BF%80%E9%85%B6%E7%BB%93%E6%9E%84%E5%9F%9F%E7%AA%81%E5%8F%98&diff=315632&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
2026-01-25T01:17:11Z
<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: 1.2px solid #e2e8f0; padding-bottom: 25px;"><br />
<p style="font-size: 1.1em; margin: 10px 0; color: #334155; text-align: justify;"><br />
<strong>ALK 激酶结构域突变</strong>（ALK Kinase Domain Mutations）是指在 ALK 阳性非小细胞肺癌（NSCLC）治疗过程中，肿瘤细胞为了逃避 ALK 酪氨酸激酶抑制剂（TKI）的杀伤，在 ALK 基因的激酶区发生的<strong>二次突变</strong>。这些突变会导致药物与靶点的结合能力下降，从而引发<strong>获得性耐药</strong>。根据发生位置的不同，主要分为<strong>守门员突变</strong>（如 [[L1196M]]）和<strong>溶剂前沿突变</strong>（如 [[G1202R]]）。不同的突变位点对不同代次的 ALK-TKI 敏感性差异巨大，因此，通过液体活检（ctDNA）明确具体的突变类型，是制定后续精准治疗方案（如换用阿来替尼、洛拉替尼）的基石。<br />
</p><br />
</div><br />
<br />
<div class="medical-infobox mw-collapsible mw-collapsed" style="width: 100%; max-width: 320px; margin: 0 auto 35px auto; 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;">ALK Mutations</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">Resistance Mechanism (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 />
[[Image:ALK_kinase_domain_mutation_map.png|100px|ALK 激酶域突变位点分布]]<br />
</div><br />
<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">耐药的“百变面孔”</div><br />
</div><br />
<br />
<table style="width: 100%; border-spacing: 0; border-collapse: collapse; font-size: 0.85em;"><br />
<tr><br />
<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">相关疾病</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">非小细胞肺癌 (NSCLC)</td><br />
</tr><br />
<tr><br />
<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">发生时机</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">TKI 治疗耐药后</td><br />
</tr><br />
<tr><br />
<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">最难治突变</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #b91c1c;"><strong>[[G1202R]]</strong> (溶剂前沿)</td><br />
</tr><br />
<tr><br />
<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">最常见突变</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">L1196M, G1269A</td><br />
</tr><br />
<tr><br />
<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">检测手段</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #166534;">NGS (组织/血液)</td><br />
</tr><br />
<tr><br />
<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">终结者药物</th><br />
<td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #166534;"><strong>[[洛拉替尼]]</strong> (第三代)</td><br />
</tr><br />
<tr><br />
<th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">特殊现象</th><br />
<td style="padding: 6px 12px; color: #0f172a;">L1198F (复敏克唑替尼)</td><br />
</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;">突变全景图谱：位点决定命运</h2><br />
<br />
<p style="margin: 15px 0; text-align: justify;"><br />
不同的突变位点对药物结合口袋的影响不同，直接决定了患者对一代、二代、三代药物的敏感性。<br />
</p><br />
<br />
<div style="overflow-x: auto; margin: 30px auto; max-width: 95%;"><br />
<table style="width: 100%; border-collapse: collapse; border: 1.2px solid #cbd5e1; font-size: 0.9em; text-align: center;"><br />
<tr style="background-color: #0f172a; color: #ffffff;"><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; width: 15%;">突变位点</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; width: 25%;">一代<br>克唑替尼</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; width: 25%;">二代<br>阿来/塞瑞/布格</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; width: 35%;">三代<br>洛拉替尼</th><br />
</tr><br />
<tr style="background-color: #f1f5f9; font-weight: bold; text-align: left;"><br />
<td colspan="4" style="padding: 8px 12px; border: 1px solid #cbd5e1; color: #475569;">I. 常见耐药突变 (Common)</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">L1196M<br>(守门员)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2; color: #b91c1c;">耐药</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">敏感</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">高度敏感</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">G1269A</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2; color: #b91c1c;">耐药</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">敏感</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">高度敏感</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">C1156Y</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2; color: #b91c1c;">耐药</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">部分敏感</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">高度敏感</td><br />
</tr><br />
<tr style="background-color: #f1f5f9; font-weight: bold; text-align: left;"><br />
<td colspan="4" style="padding: 8px 12px; border: 1px solid #cbd5e1; color: #475569;">II. 难治性突变 (Recalcitrant)</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600; color: #b91c1c;"><strong>G1202R</strong><br>(溶剂前沿)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2; color: #b91c1c;">耐药</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2; color: #b91c1c;">耐药<br>(布格替尼除外*)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;"><strong>唯一敏感</strong></td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">I1171T/N/S</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2; color: #b91c1c;">耐药</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fef9c3; color: #854d0e;">阿来耐药<br>塞瑞/布格敏感</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">高度敏感</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">1151Tins</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2; color: #b91c1c;">耐药</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2; color: #b91c1c;">耐药</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;">敏感</td><br />
</tr><br />
<tr style="background-color: #f1f5f9; font-weight: bold; text-align: left;"><br />
<td colspan="4" style="padding: 8px 12px; border: 1px solid #cbd5e1; color: #475569;">III. 特殊突变 (Paradoxical)</td><br />
</tr><br />
<tr><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600; color: #1e40af;">L1198F</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #dcfce7; color: #166534;"><strong>复敏!</strong></td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2; color: #b91c1c;">耐药 (洛拉耐药)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1; background-color: #fee2e2; color: #b91c1c;">耐药</td><br />
</tr><br />
</table><br />
<p style="font-size: 0.85em; color: #64748b; margin-top: 8px;">*注：布格替尼对 G1202R 仅有微弱抑制活性，临床上通常首选洛拉替尼。</p><br />
</div><br />
<br />
<h2 style="background: #fff1f2; color: #9f1239; padding: 10px 18px; border-radius: 0 6px 6px 0; font-size: 1.25em; margin-top: 40px; border-left: 6px solid #9f1239; font-weight: bold;">核心机制解析</h2><br />
<div style="background-color: #fff5f5; border-left: 5px solid #e11d48; padding: 15px 20px; margin: 20px 0; border-radius: 4px;"><br />
<h3 style="margin-top: 0; color: #be123c; font-size: 1.1em;">1. 溶剂前沿突变 (G1202R)</h3><br />
<p style="margin-bottom: 0; text-align: justify; font-size: 0.95em; color: #334155;"><br />
G1202R 是 ALK 耐药的“大魔王”，约占二代药物耐药病例的 50%。G1202 位于 ATP 结合口袋的溶剂暴露区。突变为精氨酸（R）后，由于引入了庞大的侧链和正电荷，产生了巨大的空间位阻和静电排斥，导致一代和二代药物完全无法结合。只有<strong>[[洛拉替尼]]</strong>（大环内酰胺结构，分子极小）能钻进这个狭小的空间发挥作用。<br />
</p><br />
</div><br />
<br />
<ul style="padding-left: 25px; color: #334155;"><br />
<li style="margin-bottom: 12px;"><strong>2. 守门员突变 ([[L1196M]])：</strong><br />
<br>位于结合口袋深处。突变后的甲硫氨酸侧链阻挡了一代药物进入，但二代、三代药物可以绕过此位阻。</li><br />
<li style="margin-bottom: 12px;"><strong>3. 复合突变 (Compound Mutations)：</strong><br />
<br>指在同一个 ALK 等位基因上同时出现两个或更多突变（如 G1202R + L1196M）。这是导致<strong>洛拉替尼耐药</strong>的主要原因，目前极为棘手，可能需要第四代药物（如 NVL-655）治疗。</li><br />
</ul><br />
<br />
<div style="font-size: 0.92em; line-height: 1.6; color: #1e293b; margin-top: 50px; border-top: 2px 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;">学术参考文献与权威点评</span><br />
<br />
<p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;"><br />
[1] <strong>Gainor JF, et al. (2016).</strong> <em>Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer.</em> <strong>[[Cancer Discovery]]</strong>.<br><br />
<span style="color: #475569;">[耐药图谱]：里程碑式研究。通过对大量临床样本的分析，绘制了不同 ALK 抑制剂耐药后的突变频率分布图，确立了 G1202R 的核心地位。</span><br />
</p><br />
<br />
<p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;"><br />
[2] <strong>Shaw AT, et al. (2016).</strong> <em>Resensitization to Crizotinib by the Lorlatinib ALK Resistance Mutation L1198F.</em> <strong>[[New England Journal of Medicine]]</strong>.<br><br />
<span style="color: #475569;">[神奇案例]：报道了 L1198F 突变导致洛拉替尼耐药，但令人惊讶地恢复了对第一代药物克唑替尼的敏感性，揭示了耐药机制的复杂动态。</span><br />
</p><br />
<br />
<p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;"><br />
[3] <strong>Katayama R, et al. (2012).</strong> <em>Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers.</em> <strong>[[Science Translational Medicine]]</strong>.<br><br />
<span style="color: #475569;">[基础机制]：详细解析了包括 L1196M, G1269A 在内的多种突变对药物结合口袋的三维结构影响。</span><br />
</p><br />
</div><br />
<br />
<div style="margin: 40px 0; border: 1px solid #e2e8f0; border-radius: 8px; overflow: hidden; font-family: 'Helvetica Neue', Arial, sans-serif; font-size: 0.9em;"><br />
<div style="background-color: #eff6ff; color: #1e40af; padding: 8px 15px; font-weight: bold; text-align: center; border-bottom: 1px solid #dbeafe;"><br />
ALK突变 · 知识图谱<br />
</div><br />
<table style="width: 100%; border-collapse: collapse; background-color: #ffffff;"><br />
<tr style="border-bottom: 1px solid #f1f5f9;"><br />
<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">突变分类</td><br />
<td style="padding: 10px 15px; color: #334155;"><strong>[[守门员突变]]</strong> (L1196M) • <strong>[[溶剂前沿突变]]</strong> (G1202R)</td><br />
</tr><br />
<tr style="border-bottom: 1px solid #f1f5f9;"><br />
<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">克唑替尼耐药</td><br />
<td style="padding: 10px 15px; color: #334155;">L1196M • G1269A • C1156Y (可用二代药解决)</td><br />
</tr><br />
<tr style="border-bottom: 1px solid #f1f5f9;"><br />
<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">阿来替尼耐药</td><br />
<td style="padding: 10px 15px; color: #334155;"><strong>[[G1202R]]</strong> (需三代) • I1171T (可用布格替尼)</td><br />
</tr><br />
<tr><br />
<td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">洛拉替尼耐药</td><br />
<td style="padding: 10px 15px; color: #334155;"><strong>[[复合突变]]</strong> (如 1202+1196) • L1198F (回用一代)</td><br />
</tr><br />
</table><br />
</div><br />
<br />
</div></div>
77921020