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WEE1 - 版本历史
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2025年12月30日 (二) 09:27 77921020
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<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;">2025年12月30日 (二) 09:27的版本</td>
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<td colspan="2" class="diff-lineno">第3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="margin-bottom: 30px; border-bottom: 1.2px solid #e2e8f0; padding-bottom: 25px;"></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="margin-bottom: 30px; border-bottom: 1.2px solid #e2e8f0; padding-bottom: 25px;"></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> <p style="font-size: 1.1em; margin: 10px 0; color: #334155; text-align: justify;"></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> <p style="font-size: 1.1em; margin: 10px 0; color: #334155; text-align: justify;"></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> <strong>WEE1</strong> 是真核细胞中高度保守的核酪氨酸激酶，被誉为细胞周期 <strong>G2/M 检查点</strong>的“守门人”。其名称源自苏格兰俚语“Wee”（微小），因为在该基因突变的酵母中，细胞在未长到足够大时就过早分裂，导致细胞体积微小。在分子层面，WEE1 通过特异性磷酸化 <strong>CDK1</strong>（CDC2）的 <strong>Tyr15</strong> 位点，抑制 CDK1-Cyclin B <del class="diffchange diffchange-inline">复合物的活性，从而阻止细胞进入有丝分裂（M </del>期）。这一机制为细胞在 DNA <del class="diffchange diffchange-inline">损伤后提供了宝贵的修复时间。在肿瘤学中，WEE1 </del>是<strong>合成致死</strong>策略的明星靶点：由于许多癌细胞（特别是 <strong>p53 突变</strong>的肿瘤）已经丧失了 G1/S <del class="diffchange diffchange-inline">检查点，它们高度依赖 </del>WEE1 介导的 G2/M 阻滞来修复 DNA。抑制 WEE1 会强行将携带 DNA 损伤的癌细胞推入 M 期，导致<strong>[[有丝分裂灾难]] (Mitotic Catastrophe)</strong> 和细胞死亡。</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> <strong>WEE1</strong> 是真核细胞中高度保守的核酪氨酸激酶，被誉为细胞周期 <strong><ins class="diffchange diffchange-inline">[[</ins>G2/M 检查点<ins class="diffchange diffchange-inline">]]</ins></strong>的“守门人”。其名称源自苏格兰俚语“Wee”（微小），因为在该基因突变的酵母中，细胞在未长到足够大时就过早分裂，导致细胞体积微小。在分子层面，WEE1 通过特异性磷酸化 <strong><ins class="diffchange diffchange-inline">[[</ins>CDK1<ins class="diffchange diffchange-inline">]]</ins></strong>（CDC2）的 <strong>Tyr15</strong> 位点，抑制 <ins class="diffchange diffchange-inline">[[</ins>CDK1<ins class="diffchange diffchange-inline">]]</ins>-<ins class="diffchange diffchange-inline">[[</ins>Cyclin B<ins class="diffchange diffchange-inline">]] 复合物的活性，从而阻止细胞进入[[有丝分裂]]（M </ins>期）。这一机制为细胞在 <ins class="diffchange diffchange-inline">[[</ins>DNA <ins class="diffchange diffchange-inline">损伤]]后提供了宝贵的修复时间。在肿瘤学中，WEE1 </ins>是<strong><ins class="diffchange diffchange-inline">[[</ins>合成致死<ins class="diffchange diffchange-inline">]]</ins></strong>策略的明星靶点：由于许多癌细胞（特别是 <strong><ins class="diffchange diffchange-inline">[[</ins>p53<ins class="diffchange diffchange-inline">]] </ins>突变</strong>的肿瘤）已经丧失了 <ins class="diffchange diffchange-inline">[[</ins>G1/S <ins class="diffchange diffchange-inline">检查点]]，它们高度依赖 </ins>WEE1 介导的 G2/M 阻滞来修复 DNA。抑制 WEE1 会强行将携带 DNA 损伤的癌细胞推入 M 期，导致<strong>[[有丝分裂灾难]] (Mitotic Catastrophe)</strong> 和细胞死亡。</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> </p></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> </p></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 colspan="2" class="diff-lineno" id="mw-diff-left-l54" >第54行：</td>
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<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> <th style="text-align: left; padding: 8px 12px; color: #475569; background-color: #f8fafc;">关键底物</th></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> <th style="text-align: left; padding: 8px 12px; color: #475569; background-color: #f8fafc;">关键底物</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> <td style="padding: 8px 12px; color: #0f172a;">CDK1 (CDC2)</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 style="padding: 8px 12px; color: #0f172a;"><ins class="diffchange diffchange-inline">[[</ins>CDK1<ins class="diffchange diffchange-inline">]] </ins>(CDC2)</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> </table></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></div></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></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> <p style="margin: 15px 0; text-align: justify;"></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> <p style="margin: 15px 0; text-align: justify;"></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> WEE1 与 CDC25 磷酸酶构成了一对精密的“阴阳”调节系统，共同决定细胞何时进入分裂期。</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> WEE1 与 <ins class="diffchange diffchange-inline">[[</ins>CDC25<ins class="diffchange diffchange-inline">]] </ins>磷酸酶构成了一对精密的“阴阳”调节系统，共同决定细胞何时进入分裂期。</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> </p></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> </p></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="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> <ul style="padding-left: 25px; color: #334155;"></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> <ul style="padding-left: 25px; color: #334155;"></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> <li style="margin-bottom: 12px;"><strong>抑制性磷酸化：</strong> 在 G2 期，WEE1 高表达并定位于细胞核。它在 CDK1 的 ATP 结合口袋上方磷酸化高度保守的 <strong>Tyr15</strong>（在某些物种中还包括 Thr14）。这个磷酸基团的空间位阻效应阻止了 ATP 的结合，从而锁住了 CDK1 的激酶活性，使细胞停留在 G2 期。</li></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> <li style="margin-bottom: 12px;"><strong>抑制性磷酸化：</strong> 在 G2 期，WEE1 高表达并定位于细胞核。它在 <ins class="diffchange diffchange-inline">[[</ins>CDK1<ins class="diffchange diffchange-inline">]] </ins>的 ATP 结合口袋上方磷酸化高度保守的 <strong>Tyr15</strong>（在某些物种中还包括 Thr14）。这个磷酸基团的空间位阻效应阻止了 ATP 的结合，从而锁住了 CDK1 的激酶活性，使细胞停留在 G2 期。</li></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> <li style="margin-bottom: 12px;"><strong>DNA 损伤响应：</strong> 当细胞检测到 DNA <del class="diffchange diffchange-inline">双链断裂时，ATM</del>/ATR 通路激活 <strong>CHK1/CHK2</strong>。CHK1 通过磷酸化 WEE1（增强其稳定性和活性）并降解 <del class="diffchange diffchange-inline">CDC25（移除其活性），双管齐下地强化 </del>G2/M 检查点，防止细胞带着受损的 DNA 进行分裂。</li></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> <li style="margin-bottom: 12px;"><strong>DNA 损伤响应：</strong> 当细胞检测到 <ins class="diffchange diffchange-inline">[[</ins>DNA <ins class="diffchange diffchange-inline">双链断裂]]时，[[ATM]]</ins>/<ins class="diffchange diffchange-inline">[[</ins>ATR<ins class="diffchange diffchange-inline">]] </ins>通路激活 <strong><ins class="diffchange diffchange-inline">[[</ins>CHK1<ins class="diffchange diffchange-inline">]]</ins>/<ins class="diffchange diffchange-inline">[[</ins>CHK2<ins class="diffchange diffchange-inline">]]</ins></strong>。CHK1 通过磷酸化 WEE1（增强其稳定性和活性）并降解 <ins class="diffchange diffchange-inline">[[CDC25]]（移除其活性），双管齐下地强化 </ins>G2/M 检查点，防止细胞带着受损的 DNA 进行分裂。</li></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> <li style="margin-bottom: 12px;"><strong>有丝分裂灾难：</strong> 如果在 DNA 未修复的情况下人为抑制 WEE1，CDK1 会被过早激活（Premature <del class="diffchange diffchange-inline">activation）。细胞被迫进入有丝分裂，导致染色体分离异常、微核形成，最终引发一种特殊的细胞死亡形式——有丝分裂灾难或崩塌。</del></li></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> <li style="margin-bottom: 12px;"><strong>有丝分裂灾难：</strong> 如果在 DNA 未修复的情况下人为抑制 WEE1，CDK1 会被过早激活（Premature <ins class="diffchange diffchange-inline">activation）。细胞被迫进入有丝分裂，导致[[染色体分离]]异常、微核形成，最终引发一种特殊的细胞死亡形式——[[有丝分裂灾难]]或崩塌。</ins></li></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> </ul></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> </ul></div></td></tr>
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<tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l84" >第84行：</td>
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<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 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 style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">浆液性子宫内膜癌 (USC)</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 style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;"><ins class="diffchange diffchange-inline">[[</ins>浆液性子宫内膜癌<ins class="diffchange diffchange-inline">]] </ins>(USC)</td></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 style="padding: 10px; border: 1px solid #cbd5e1;">CCNE1 高扩增 / p53 突变</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 style="padding: 10px; border: 1px solid #cbd5e1;"><ins class="diffchange diffchange-inline">[[</ins>CCNE1<ins class="diffchange diffchange-inline">]] </ins>高扩增 / <ins class="diffchange diffchange-inline">[[</ins>p53<ins class="diffchange diffchange-inline">]] </ins>突变</td></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 style="padding: 10px; border: 1px solid #cbd5e1;"><del class="diffchange diffchange-inline">这类肿瘤存在极高的复制压力（Replication </del>Stress），高度依赖 WEE1 <del class="diffchange diffchange-inline">来防止复制崩溃。Adavosertib </del>单药在该难治性亚型中显示出令人鼓舞的客观缓解率（~30%）。</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 style="padding: 10px; border: 1px solid #cbd5e1;"><ins class="diffchange diffchange-inline">这类肿瘤存在极高的[[复制压力]]（Replication </ins>Stress），高度依赖 WEE1 <ins class="diffchange diffchange-inline">来防止复制崩溃。[[Adavosertib]] </ins>单药在该难治性亚型中显示出令人鼓舞的客观缓解率（~30%）。</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 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 style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">卵巢癌</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 style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;"><ins class="diffchange diffchange-inline">[[</ins>卵巢癌<ins class="diffchange diffchange-inline">]]</ins></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> <td style="padding: 10px; border: 1px solid #cbd5e1;">p53 突变 / PARP 耐药</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;">p53 突变 / PARP 耐药</td></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 style="padding: 10px; border: 1px solid #cbd5e1;">在铂耐药或 PARP <del class="diffchange diffchange-inline">抑制剂耐药的卵巢癌中，WEE1 抑制剂与化疗（如吉西他滨、卡铂）联用，旨在通过破坏 </del>G2 检查点来增敏化疗药物引起的 DNA 损伤。</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 style="padding: 10px; border: 1px solid #cbd5e1;">在铂耐药或 <ins class="diffchange diffchange-inline">[[</ins>PARP <ins class="diffchange diffchange-inline">抑制剂]]耐药的卵巢癌中，WEE1 抑制剂与化疗（如[[吉西他滨]]、[[卡铂]]）联用，旨在通过破坏 </ins>G2 检查点来增敏化疗药物引起的 DNA 损伤。</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 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 style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">胰腺癌 / 结直肠癌</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 style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;"><ins class="diffchange diffchange-inline">[[</ins>胰腺癌<ins class="diffchange diffchange-inline">]] </ins>/ <ins class="diffchange diffchange-inline">[[</ins>结直肠癌<ins class="diffchange diffchange-inline">]]</ins></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> <td style="padding: 10px; border: 1px solid #cbd5e1;">联合放化疗</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;">联合放化疗</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> <td style="padding: 10px; border: 1px solid #cbd5e1;">WEE1 抑制剂作为<strong>放疗增敏剂</strong>正在进行探索，因为放疗主要引起 DNA 损伤，阻断修复检查点可显著提高放疗杀伤力。</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;">WEE1 抑制剂作为<strong>放疗增敏剂</strong>正在进行探索，因为放疗主要引起 DNA 损伤，阻断修复检查点可显著提高放疗杀伤力。</td></div></td></tr>
<tr><td colspan="2" class="diff-lineno" id="mw-diff-left-l110" >第110行：</td>
<td colspan="2" class="diff-lineno">第110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> <br><strong>[[Adavosertib]]</strong> (AZD1775 / MK-1775)。</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> <br><strong>[[Adavosertib]]</strong> (AZD1775 / MK-1775)。</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> <br><span style="font-size: 0.9em; color: #64748b;">*地位：临床进展最快的 WEE1 高选择性抑制剂。</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> <br><span style="font-size: 0.9em; color: #64748b;">*地位：临床进展最快的 WEE1 高选择性抑制剂。</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> <br>*<del class="diffchange diffchange-inline">挑战：主要的剂量限制性毒性是骨髓抑制（中性粒细胞减少、贫血）和腹泻，这限制了其与强效化疗药联合时的剂量强度。</del></span></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> <br>*<ins class="diffchange diffchange-inline">挑战：主要的剂量限制性毒性是[[骨髓抑制]]（中性粒细胞减少、贫血）和腹泻，这限制了其与强效化疗药联合时的剂量强度。</ins></span></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> </li></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> </li></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> <li style="margin-bottom: 12px;"><strong>合成致死组合：</strong></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> <li style="margin-bottom: 12px;"><strong>合成致死组合：</strong></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> <br><strong>WEE1i + <del class="diffchange diffchange-inline">PARPi：</del></strong> PARP 抑制剂导致单链断裂积累，增加复制压力；WEE1 抑制剂阻止 G2 期修复。两者联用在 BRCA <del class="diffchange diffchange-inline">突变及其他同源重组缺陷（HRD）肿瘤中显示协同效应。</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> <br><strong>WEE1i + <ins class="diffchange diffchange-inline">[[PARPi]]：</ins></strong> PARP 抑制剂导致单链断裂积累，增加复制压力；WEE1 抑制剂阻止 G2 期修复。两者联用在 <ins class="diffchange diffchange-inline">[[</ins>BRCA<ins class="diffchange diffchange-inline">]] 突变及其他[[同源重组缺陷]]（HRD）肿瘤中显示协同效应。</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> <br><strong>WEE1i + <del class="diffchange diffchange-inline">ATRi：</del></strong> ATR 和 WEE1 串联工作于 G2/M 检查点，双重阻断可彻底摧毁肿瘤的 DNA 损伤应答机制。</li></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> <br><strong>WEE1i + <ins class="diffchange diffchange-inline">[[ATRi]]：</ins></strong> ATR 和 WEE1 串联工作于 G2/M 检查点，双重阻断可彻底摧毁肿瘤的 DNA 损伤应答机制。</li></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> </ul></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> </ul></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 colspan="2" class="diff-lineno" id="mw-diff-left-l122" >第122行：</td>
<td colspan="2" class="diff-lineno">第122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> <li style="margin-bottom: 12px;"><strong>[[p53]]：</strong> 其功能缺失是 WEE1 抑制剂发挥疗效的前提（合成致死）。</li></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> <li style="margin-bottom: 12px;"><strong>[[p53]]：</strong> 其功能缺失是 WEE1 抑制剂发挥疗效的前提（合成致死）。</li></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> <li style="margin-bottom: 12px;"><strong>[[CDK1]]：</strong> WEE1 的直接底物和抑制对象。</li></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> <li style="margin-bottom: 12px;"><strong>[[CDK1]]：</strong> WEE1 的直接底物和抑制对象。</li></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> <li style="margin-bottom: 12px;"><strong><del class="diffchange diffchange-inline">CCNE1扩增：</del></strong> 预测 WEE1 抑制剂敏感性的重要生物标志物。</li></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> <li style="margin-bottom: 12px;"><strong><ins class="diffchange diffchange-inline">[[CCNE1]]扩增：</ins></strong> 预测 WEE1 抑制剂敏感性的重要生物标志物。</li></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> </ul></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> </ul></div></td></tr>
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77921020
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2025-12-30T09:25:23Z
<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 />
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<strong>WEE1</strong> 是真核细胞中高度保守的核酪氨酸激酶，被誉为细胞周期 <strong>G2/M 检查点</strong>的“守门人”。其名称源自苏格兰俚语“Wee”（微小），因为在该基因突变的酵母中，细胞在未长到足够大时就过早分裂，导致细胞体积微小。在分子层面，WEE1 通过特异性磷酸化 <strong>CDK1</strong>（CDC2）的 <strong>Tyr15</strong> 位点，抑制 CDK1-Cyclin B 复合物的活性，从而阻止细胞进入有丝分裂（M 期）。这一机制为细胞在 DNA 损伤后提供了宝贵的修复时间。在肿瘤学中，WEE1 是<strong>合成致死</strong>策略的明星靶点：由于许多癌细胞（特别是 <strong>p53 突变</strong>的肿瘤）已经丧失了 G1/S 检查点，它们高度依赖 WEE1 介导的 G2/M 阻滞来修复 DNA。抑制 WEE1 会强行将携带 DNA 损伤的癌细胞推入 M 期，导致<strong>[[有丝分裂灾难]] (Mitotic Catastrophe)</strong> 和细胞死亡。<br />
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<div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">WEE1 · 基因档案</div><br />
<div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">Gene & Protein Profile (点击展开)</div><br />
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[[文件:WEE1_G2M_Checkpoint.png|100px|WEE1 调控 G2/M 检查点]]<br />
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<div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">G2期激酶 / 合成致死靶点</div><br />
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<th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #475569; background-color: #f8fafc; width: 40%;">基因符号</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #0f172a;"><strong>WEE1</strong></td><br />
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<th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #475569; background-color: #f8fafc;">全称</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #0f172a;">WEE1 G2 checkpoint kinase</td><br />
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<th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #475569; background-color: #f8fafc;">染色体位置</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #0f172a;">11p15.4</td><br />
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<th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #475569; background-color: #f8fafc;">Entrez ID</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #1e40af;">7465</td><br />
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<th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #475569; background-color: #f8fafc;">HGNC ID</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #1e40af;">12761</td><br />
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<th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #475569; background-color: #f8fafc;">UniProt</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #1e40af;">P30291</td><br />
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<th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #475569; background-color: #f8fafc;">分子量</th><br />
<td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9; color: #0f172a;">~96 kDa</td><br />
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<th style="text-align: left; padding: 8px 12px; color: #475569; background-color: #f8fafc;">关键底物</th><br />
<td style="padding: 8px 12px; color: #0f172a;">CDK1 (CDC2)</td><br />
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<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：有丝分裂的刹车片</h2><br />
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WEE1 与 CDC25 磷酸酶构成了一对精密的“阴阳”调节系统，共同决定细胞何时进入分裂期。<br />
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<li style="margin-bottom: 12px;"><strong>抑制性磷酸化：</strong> 在 G2 期，WEE1 高表达并定位于细胞核。它在 CDK1 的 ATP 结合口袋上方磷酸化高度保守的 <strong>Tyr15</strong>（在某些物种中还包括 Thr14）。这个磷酸基团的空间位阻效应阻止了 ATP 的结合，从而锁住了 CDK1 的激酶活性，使细胞停留在 G2 期。</li><br />
<li style="margin-bottom: 12px;"><strong>DNA 损伤响应：</strong> 当细胞检测到 DNA 双链断裂时，ATM/ATR 通路激活 <strong>CHK1/CHK2</strong>。CHK1 通过磷酸化 WEE1（增强其稳定性和活性）并降解 CDC25（移除其活性），双管齐下地强化 G2/M 检查点，防止细胞带着受损的 DNA 进行分裂。</li><br />
<li style="margin-bottom: 12px;"><strong>有丝分裂灾难：</strong> 如果在 DNA 未修复的情况下人为抑制 WEE1，CDK1 会被过早激活（Premature activation）。细胞被迫进入有丝分裂，导致染色体分离异常、微核形成，最终引发一种特殊的细胞死亡形式——有丝分裂灾难或崩塌。</li><br />
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<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;">临床景观：p53 缺失肿瘤的阿喀琉斯之踵</h2><br />
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WEE1 抑制剂的开发主要利用了肿瘤细胞对 G2 检查点的过度依赖性。<br />
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<th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">应用场景</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">分子逻辑</th><br />
<th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">临床进展</th><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">浆液性子宫内膜癌 (USC)</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">CCNE1 高扩增 / p53 突变</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">这类肿瘤存在极高的复制压力（Replication Stress），高度依赖 WEE1 来防止复制崩溃。Adavosertib 单药在该难治性亚型中显示出令人鼓舞的客观缓解率（~30%）。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">卵巢癌</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">p53 突变 / PARP 耐药</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">在铂耐药或 PARP 抑制剂耐药的卵巢癌中，WEE1 抑制剂与化疗（如吉西他滨、卡铂）联用，旨在通过破坏 G2 检查点来增敏化疗药物引起的 DNA 损伤。</td><br />
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<td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">胰腺癌 / 结直肠癌</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">联合放化疗</td><br />
<td style="padding: 10px; border: 1px solid #cbd5e1;">WEE1 抑制剂作为<strong>放疗增敏剂</strong>正在进行探索，因为放疗主要引起 DNA 损伤，阻断修复检查点可显著提高放疗杀伤力。</td><br />
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<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;">治疗策略：Adavosertib 与联合致死</h2><br />
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目前 WEE1 抑制剂多处于临床试验阶段，核心策略是“联合增效”。<br />
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<li style="margin-bottom: 12px;"><strong>小分子抑制剂：</strong><br />
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<br><strong>[[Adavosertib]]</strong> (AZD1775 / MK-1775)。<br />
<br><span style="font-size: 0.9em; color: #64748b;">*地位：临床进展最快的 WEE1 高选择性抑制剂。<br />
<br>*挑战：主要的剂量限制性毒性是骨髓抑制（中性粒细胞减少、贫血）和腹泻，这限制了其与强效化疗药联合时的剂量强度。</span><br />
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<li style="margin-bottom: 12px;"><strong>合成致死组合：</strong><br />
<br><strong>WEE1i + PARPi：</strong> PARP 抑制剂导致单链断裂积累，增加复制压力；WEE1 抑制剂阻止 G2 期修复。两者联用在 BRCA 突变及其他同源重组缺陷（HRD）肿瘤中显示协同效应。<br />
<br><strong>WEE1i + ATRi：</strong> ATR 和 WEE1 串联工作于 G2/M 检查点，双重阻断可彻底摧毁肿瘤的 DNA 损伤应答机制。</li><br />
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<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;">关键关联概念</h2><br />
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<li style="margin-bottom: 12px;"><strong>[[有丝分裂灾难]]：</strong> 抑制 WEE1 导致的主要细胞死亡方式。</li><br />
<li style="margin-bottom: 12px;"><strong>[[p53]]：</strong> 其功能缺失是 WEE1 抑制剂发挥疗效的前提（合成致死）。</li><br />
<li style="margin-bottom: 12px;"><strong>[[CDK1]]：</strong> WEE1 的直接底物和抑制对象。</li><br />
<li style="margin-bottom: 12px;"><strong>CCNE1扩增：</strong> 预测 WEE1 抑制剂敏感性的重要生物标志物。</li><br />
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<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 />
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[1] <strong>Nurse P. (1975).</strong> <em>Genetic control of cell size at cell division in yeast.</em> <strong>Nature</strong>. <br><br />
<span style="color: #475569;">[学术点评]：诺奖工作。Paul Nurse 首次在裂殖酵母中鉴定了 wee1 基因，发现其突变导致细胞过早分裂，确立了其作为有丝分裂负调控因子的地位。</span><br />
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<p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;"><br />
[2] <strong>Igarashi M, et al. (1991).</strong> <em>Cloning and expression of a human protein kinase with homology to the fission yeast wee1+ gene.</em> <strong>Nature</strong>. <br><br />
<span style="color: #475569;">[学术点评]：人类同源物。克隆了人类 WEE1 基因，并证实其能挽救酵母的 wee1 缺陷表型，证明了细胞周期调控机制在进化上的高度保守性。</span><br />
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<p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;"><br />
[3] <strong>Hirai H, et al. (2009).</strong> <em>Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents.</em> <strong>Molecular Cancer Therapeutics</strong>. <br><br />
<span style="color: #475569;">[学术点评]：合成致死验证。首次报道了 MK-1775 (Adavosertib) 的药理学特征，并证实了其对 p53 缺失肿瘤的选择性杀伤作用，为后续临床试验奠定了基础。</span><br />
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<p style="margin: 12px 0; border-bottom: 1px solid #e2e8f0; padding-bottom: 10px;"><br />
[4] <strong>Liu JF, et al. (2021).</strong> <em>Adavosertib in patients with uterine serous carcinoma: A multicenter phase II trial.</em> <strong>Journal of Clinical Oncology (JCO)</strong>. <br><br />
<span style="color: #475569;">[学术点评]：临床突破。证明 Adavosertib 单药在 CCNE1 扩增的复发性子宫浆液性癌中具有显著疗效，该研究可能推动 WEE1 抑制剂的首个适应症获批。</span><br />
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[5] <strong>Matheson CJ, et al. (2016).</strong> <em>Targeting WEE1 Kinase in Cancer.</em> <strong>Trends in Pharmacological Sciences</strong>. <br><br />
<span style="color: #475569;">[学术点评]：综述。全面总结了 WEE1 在 G2/M 检查点和复制压力应答中的双重角色，以及其抑制剂与其他 DDR 靶向药物联用的理论依据。</span><br />
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<div style="background-color: #0f172a; color: #ffffff; text-align: center; font-weight: bold; padding: 10px; letter-spacing: 1px;">WEE1 · 知识图谱关联</div><br />
<div style="padding: 15px; background: #ffffff; line-height: 2.2; text-align: center; text-decoration: none;"><br />
[[有丝分裂灾难]] • [[Adavosertib]] • [[p53]] • [[G2/M检查点]] • [[CDK1]] • [[子宫浆液性癌]] • [[合成致死]] • [[CDC25]]<br />
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77921020