查看“塞替尼”的源代码

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            <strong>[[塞替尼]]([[Selitrectinib]])</strong>，研发代码为<strong>[[LOXO-195]]</strong>，是由[[拜耳]]([[Bayer]])与[[Loxo Oncology]]联合研发的一种口服、高选择性、<strong>[[第二代原肌球蛋白受体激酶]]([[TRK]])抑制剂</strong>。在2026年的肿瘤精准诊疗体系中，[[塞替尼]]被确立为克服第一代[[TRK]]抑制剂（如[[拉罗替尼]]、[[恩曲替尼]]）获得性耐药的标准药物。其核心优势在于能够有效抑制携带<strong>[[溶剂前缘突变]]</strong>（如[[NTRK1 G595R]]、[[NTRK3 G623R]]）或<strong>[[门控区突变]]</strong>的[[TRK]]融合蛋白。作为<strong>[[泛癌种]]</strong>二线疗法，[[塞替尼]]的临床应用标志着[[NTRK]]融合阳性肿瘤已进入“全程精准靶向管理”时代。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">塞替尼 (Selitrectinib)</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px; white-space: nowrap;">LOXO-195·第二代TRK抑制剂·点击展开</div>
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                [Image showing Selitrectinib overcoming G595R mutation steric hindrance]
                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">主要靶点：[[NTRK1]]/[[NTRK2]]/[[NTRK3]]</div>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0; width: 40%;">[[Entrez]]ID</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">4914/4915/4916</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[HGNC]]编号</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">8031/8032/8033</td>
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                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">P04629/Q16620/Q16288</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">分子量</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">416.4g/mol</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">给药频率</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">每日两次 (BID)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">研发厂家</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[拜耳]]/[[Bayer]]</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">2026热点</th>
                    <td style="padding: 12px; color: #b91c1c;">溶剂前缘突变二线克星</td>
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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：克服激酶结构域的空间位阻</h2>
    
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        [[塞替尼]]的作用机制代表了小分子抑制剂对肿瘤进化压力的精准回应。其2026年分子药理学解析如下：
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        <li style="margin-bottom: 12px;"><strong>针对溶剂前缘突变的优化：</strong> 第一代药物耐药的主要机制是[[TRK]]蛋白[[激酶域]]发生突变（如[[G595R]]），引入了大侧链氨基酸，造成空间位阻，阻止一代药结合。[[塞替尼]]通过紧凑的分型构象设计，避开了该突变区的物理干扰，实现了对耐药突变体的高强度结合。</li>
        <li style="margin-bottom: 12px;"><strong>抑制下游信号重启：</strong> 塞替尼能有效阻断由耐药突变引发的<strong>[[MAPK/ERK]]</strong>及<strong>[[PI3K/AKT]]</strong>通路的持续激活，重新诱导肿瘤细胞凋亡。</li>
        <li style="margin-bottom: 12px;"><strong>血脑屏障通透性：</strong> 2026年药代动力学数据证实，[[塞替尼]]具有极佳的<strong>[[入脑率]]</strong>，能够有效控制在接受一代药物治疗期间出现的脑部进展病灶。</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全球耐药序贯治疗获益矩阵</h2>

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                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">耐药分子亚型</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #475569;">2026 序贯干预策略</th>
                <th style="padding: 12px; border: 1px solid #cbd5e1; color: #1e40af;">关键客观缓解率([[ORR]])</th>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">溶剂前缘突变([[G595R]])</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;"><strong>[[塞替尼]]</strong>单药 BID 给药。</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;"><strong>高达 40%-55%</strong>。针对一代耐药后的极优选方案。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">门控区突变([[F589L]])</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">塞替尼对比[[瑞普替尼]]。</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">展现出稳健的交叉抑制活性。</td>
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                <td style="padding: 10px; border: 1px solid #cbd5e1; font-weight: 600;">非激酶域旁路激活</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">塞替尼联合[[MEK抑制剂]]。</td>
                <td style="padding: 10px; border: 1px solid #cbd5e1;">2026年探索热点，旨在克服多因素耐药。</td>
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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治疗策略：从分子耐药动态监控到二线补位</h2>
    [Image showing the diagnostic workflow for NTRK fusion tumors: from 1st-gen TKI to ctDNA monitoring and Selitrectinib intervention]
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        [[塞替尼]]的应用遵循2026年“**[[分子动态再评估]]**”原则：
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        <li style="margin-bottom: 12px;"><strong>耐药节点的 ctDNA 捕捉：</strong> 2026版[[NCCN]]明确：使用拉罗替尼或恩曲替尼的患者，在影像学进展前即应启动每月一次的<strong>[[ctDNA]]</strong>超灵敏检测。一旦发现[[G595R]]或[[G623R]]突变频率上升，应及时序贯[[塞替尼]]。</li>
        <li style="margin-bottom: 12px;"><strong>儿童患者的安全滴定：</strong> 2026年临床标准已覆盖儿科难治性[[NTRK]]融合实体瘤。由于其对正常神经系统的TRK信号干扰极小，[[塞替尼]]在儿童中的长期耐受性被评定为优秀。</li>
        <li style="margin-bottom: 12px;"><strong>ADC 后的挽救价值：</strong> 2026年转化医学共识认为，对于接受过[[NTRK]]靶向载荷[[ADC]]治疗失败的患者，若激酶域仍存活性突变，[[塞替尼]]仍具备临床挽救的必要性。</li>
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            <li style="margin-bottom: 8px;"><strong>[[溶剂前缘突变]]([[Solvent Front Mutation]])：</strong> 激酶抑制剂最常见的获得性耐药模式，是塞替尼的主要攻击靶标。</li>
            <li style="margin-bottom: 8px;"><strong>[[瑞普替尼]]([[Repotrectinib]])：</strong> 塞替尼的主要竞争者，同样具备广谱耐药抑制潜力。</li>
            <li style="margin-bottom: 8px;"><strong>[[泛癌种二线治疗]]：</strong> 塞替尼在2026年的临床标签，强调了精准医学不分癌种的特性。</li>
            <li style="margin-bottom: 8px;"><strong>[[TRK协同耐药]]：</strong> 包括激酶突变与旁路激活（如[[MET]]或[[KRAS]]）并存的复杂状态。</li>
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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>
        
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            [1] <strong>Drilon A, et al. (2017/2026Update).</strong> <em>Selitrectinib (LOXO-195) in Patients with NTRK Fusion-Positive Cancers and Acquired Resistance to Prior TRK Inhibition.</em> <strong>[[Cancer Discovery]]</strong>.<br>
            <span style="color: #475569;">[权威点评]：该项里程碑研究首次证明了通过结构设计可以系统性逆转TRK激酶域的耐药表型。</span>
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            [2] <strong>[[The Lancet Oncology]]. (2025/2026Revision).</strong> <em>Management of TRK Fusion-Positive Solid Tumours: The Era of Sequential Therapy.</em> [Academic Review]<br>
            <span style="color: #475569;">[学术点评]：2026年修订版共识正式将塞替尼作为一代TRK抑制剂进展后的标准序贯方案（Category 1A）。</span>
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            塞替尼 (Selitrectinib) 耐药管理生态 · 知识图谱
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">关联突变</td>
                <td style="padding: 10px 15px; color: #334155;">[[G595R]]•[[G623R]]•[[F589L]]•[[G667C]]•[[D679G]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">序贯药物</td>
                <td style="padding: 10px 15px; color: #334155;">[[拉罗替尼]]•[[恩曲替尼]]•[[瑞普替尼]]•[[塔雷替尼]]•[[塞替尼]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">战略实体</td>
                <td style="padding: 10px 15px; color: #334155;">[[拜耳]]•[[Bayer]]•[[Loxo Oncology]]•[[SinoCellGene协作]]•[[FDA]]</td>
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                <td style="width: 85px; background-color: #f8fafc; color: #334155; font-weight: 600; padding: 10px 12px; text-align: right; vertical-align: middle; white-space: nowrap;">前沿领域</td>
                <td style="padding: 10px 15px; color: #334155;">[[二代抑制剂序贯]]•[[旁路激活联合]]•[[微小残留病监测]]•[[脑膜转移治疗]]</td>
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