查看“二代 RAFi”的源代码

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            <strong>[[RAF 抑制剂]] ([[RAFi]])</strong> 是一类高选择性的[[小分子激酶抑制剂]]，通过竞争性结合 <strong>[[RAF 激酶]]</strong>（包括 [[ARAF]]、[[BRAF]]、[[CRAF]]）的 [[ATP 结合位点]]，阻断 <strong>[[MAPK/ERK 通路]]</strong> 的异常激活。作为 2026 年[[精准肿瘤学]]的基石药物，RAFi 经历了从针对 <strong>[[BRAF V600E]]</strong> [[I 类突变]]的单体抑制剂，向能够同时靶向[[二聚体]]且规避 <strong>[[矛盾激活]]</strong> 的[[二代 RAF 抑制剂]]（Type II/Pan-RAF）的重大演进。其在 <strong>[[黑色素瘤]]</strong>、<strong>[[甲状腺乳头状癌]]</strong> 及 <strong>[[结直肠癌]]</strong> 的多靶点联合治疗中具有不可替代的临床地位。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">RAF 抑制剂档案</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">机制：[[ATP 竞争性抑制]]</div>
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                <tr><th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; background-color: #f8fafc; width: 40%;">药物大类</th><td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9;">[[抗肿瘤药]] / [[TKI]]</td></tr>
                <tr><th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; background-color: #f8fafc;">核心靶点</th><td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9;">[[BRAF]], [[CRAF]]</td></tr>
                <tr><th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; background-color: #f8fafc;">分代演进</th><td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9;">[[Type I]], [[Type II]]</td></tr>
                <tr><th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; background-color: #f8fafc;">耐药标志</th><td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9;">[[MEK 突变]], [[MET 扩增]]</td></tr>
                <tr><th style="text-align: left; padding: 8px 12px; border-bottom: 1px solid #f1f5f9; background-color: #f8fafc;">2026 指南</th><td style="padding: 8px 12px; border-bottom: 1px solid #f1f5f9;">[[NCCN]] / [[CSCO]]</td></tr>
                <tr><th style="text-align: left; padding: 8px 12px; background-color: #f8fafc;">联用金标准</th><td style="padding: 8px 12px; color: #1e40af; font-weight: bold;">[[RAFi]] + [[MEKi]]</td></tr>
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        RAFi 的治疗效应取决于其对激酶构象的选择性。2026 年的研究强调了<strong>[[构象特异性抑制]]</strong>对预后的影响：
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        <li style="margin-bottom: 12px;"><strong>[[I 类抑制剂]]（Type I/I.5）：</strong> 以 <strong>[[达拉非尼]]</strong> 为代表。它们优先结合激酶的 <strong>[[DFG-in 构象]]</strong>。虽然对 V600E 单体有效，但在野生型细胞中会诱发 <strong>[[矛盾激活]]</strong>，通过 [[跨二聚体激活]] 导致[[皮肤鳞状细胞癌]]等不良反应。</li>
        <li style="margin-bottom: 12px;"><strong>[[II 类抑制剂]]（Type II）：</strong> 以 <strong>[[Belvarafenib]]</strong> 为代表。它们结合 <strong>[[DFG-out 构象]]</strong>，能有效阻断 <strong>[[BRAF 融合]]</strong> 或 <strong>[[II 类突变]]</strong> 产生的强力二聚体信号，且极少引发矛盾激活。</li>
        <li style="margin-bottom: 12px;"><strong>[[反馈回路重塑]]：</strong> 抑制 RAF 往往导致 <strong>[[EGFR]]</strong> 或 <strong>[[HER3]]</strong> 的代偿性上调。2026 版治疗策略强调需通过 <strong>[[垂直阻断]]</strong>（联合 [[MEK 抑制剂]]）来中和这些[[信号逃逸]]。</li>
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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;">2026 临床应用与循证矩阵</h2>
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                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a;">药物名称</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">突变分型选择</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">2026 临床证据/研究</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[达拉非尼]] (Dabrafenib)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">[[V600E/K]] (I 类)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">联合曲美替尼，确认在[[不限癌种治疗]]中的长期获益。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[恩考非尼]] (Encorafenib)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">[[V600E]] (CRC)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;"><strong>[[BEACON 方案]]</strong>：联合西妥昔单抗显著提升 mOS。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">[[Tovorafenib]] (DAY101)</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">[[BRAF 融合]] / [[II 类变异]]</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">2026 获批：<strong>[[儿童低级别胶质瘤]]</strong> (pLGG) 一线标准治疗。</td>
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            [[MAPK 级联]] • [[信号反馈抑制]] • [[NRAS 突变]] • [[垂直封锁策略]] • [[MEK 抑制剂]] • [[别构抑制]] • [[细胞凋亡]]
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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 [Academic Review]</span>
        
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            [1] <strong>Hatzivassiliou G, et al. (2010).</strong> <em>RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.</em> <strong>[[Nature]]</strong>. 464(7287):431-5.<br>
            <span style="color: #475569;">[点评]：经典研究，首次科学界定了“矛盾激活”现象的分子基础。</span>
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            [2] <strong>Flaherty KT, et al. (2012).</strong> <em>Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.</em> <strong>[[The New England Journal of Medicine]]</strong>. 367:1694-1703.<br>
            <span style="color: #475569;">[点评]：双靶联用的里程碑试验，确立了目前全球范围内 MAPK 通路标准的临床用药范式。</span>
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            [3] <strong>Subbiah V, et al. (2025).</strong> <em>Next-generation Pan-RAF inhibitors: Overcoming resistance in BRAF-fusion and non-V600 mutant cancers.</em> <strong>[[Nature Reviews Clinical Oncology]]</strong>.<br>
            <span style="color: #475569;">[点评]：2025 年最新综述，系统梳理了二代抑制剂在复杂 BRAF 变异中的药理学优势与生存获益数据。</span>
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            RAF 抑制剂 · 知识图谱关联系统
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                <td style="width: 95px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">核心靶点</td>
                <td style="padding: 10px 15px; color: #334155;">[[BRAF]] • [[CRAF]] • [[MEK1/2]] • [[KIAA1549-BRAF]]</td>
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                <td style="width: 95px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">代表药物</td>
                <td style="padding: 10px 15px; color: #334155;">[[Dabrafenib]] • [[Encorafenib]] • [[Belvarafenib]] • [[Tovorafenib]]</td>
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                <td style="width: 95px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">耐药/旁路</td>
                <td style="padding: 10px 15px; color: #334155;">[[EGFR 反馈]] • [[HER3 激活]] • [[MET 扩增]] • [[NRAS 突变]]</td>
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                <td style="width: 95px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right;">研究机构</td>
                <td style="padding: 10px 15px; color: #334155;">[[SinoCellGene]] • [[Dana-Farber]] • [[ASCO]] • [[ESMO]]</td>
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