查看“L858R突变”的源代码

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            <strong>[[L858R突变]]</strong>（[[EGFR Exon 21 L858R]]）是[[表皮生长因子受体]]（[[EGFR]]）基因第[[21号外显子]]上最常见的[[点突变]]。该突变导致[[激酶结构域]]第858位的[[亮氨酸]]（L）被[[精氨酸]]（R）取代，进而引起[[EGFR]]蛋白的持续性激活。作为[[非小细胞肺癌]]（[[NSCLC]]）中第二大[[敏感突变]]（约占所有[[EGFR]]突变的40%），[[L858R突变]]在[[东亚]]人群、非吸烟者及女性患者中高发。在2026年的临床实践中，[[L858R突变]]被公认为[[EGFR-TKI]]（[[酪氨酸激酶抑制剂]]）治疗的关键[[生物标志物]]，虽然其对药物的总体响应率极高，但其[[预后]]表现与[[19号外显子缺失]]（[[19-Del]]）存在显著的生物学差异。
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            <div style="font-size: 1.2em; font-weight: bold; letter-spacing: 1.2px;">[[L858R突变]]</div>
            <div style="font-size: 0.7em; opacity: 0.85; margin-top: 4px;">[[EGFR Exon 21 L858R]] · 点击展开详情</div>
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                <div style="font-size: 0.8em; color: #64748b; margin-top: 12px; font-weight: 600;">[[蛋白质]]改变：p.Leu858Arg</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;">1956([[EGFR]])</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[突变]]类型</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[错义突变]]</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">发生频率</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">约40% (EGFR+)</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[靶向药物]]</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #1e40af;">[[第一至三代TKI]]</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569; border-bottom: 1px solid #e2e8f0;">[[检测方法]]</th>
                    <td style="padding: 6px 12px; border-bottom: 1px solid #e2e8f0; color: #0f172a;">[[PCR]]/[[NGS]]</td>
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                    <th style="text-align: left; padding: 6px 12px; background-color: #f1f5f9; color: #475569;">相关[[病理]]</th>
                    <td style="padding: 12px; color: #0f172a;">[[肺腺癌]]</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：激酶结构的构象激活</h2>
    
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        [[L858R突变]]通过改变[[EGFR]]激酶结构域的物理特性，打破了受体激活的稳态平衡：
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        <li style="margin-bottom: 12px;"><strong>[[激活环]]（A-loop）失稳：</strong>正常情况下，L858位点位于[[激酶结构域]]的[[激活环]]起始处。突变后的[[精氨酸]]（R）带有电荷且体积较大，会破坏[[失活状态]]下的疏水相互作用，使[[激活环]]更倾向于维持在[[开放构象]]，即[[活性状态]]。</li>
        <li style="margin-bottom: 12px;"><strong>[[ATP结合位点]]改变：</strong>突变显著增强了受体对[[三磷酸腺苷]]（[[ATP]]）的结合亲和力，同时降低了对内源性抑制信号的敏感性，导致下游[[MAPK通路]]和[[PI3K/Akt通路]]的持续[[磷酸化]]激活。</li>
        <li style="margin-bottom: 12px;"><strong>[[二聚化]]不依赖：</strong>虽然配体结合仍有增强作用，但[[L858R突变]]体在无配体存在时即可发生自发性的[[异源二聚化]]或[[同源二聚化]]。</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;">临床特征对比：L858R vs 19-Del</h2>

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                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #0f172a; width: 25%;">特征维度</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #475569;">[[L858R突变]]</th>
                <th style="padding: 10px; border: 1px solid #cbd5e1; color: #1e40af;">[[19号外显子缺失]]</th>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[生物学活性]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">相对较低的[[激酶活性]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">极高的[[激酶活性]]</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[TKI]]治疗[[PFS]]</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">通常较短（约9-12个月）</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">较长（约12-19个月）</td>
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                <td style="padding: 8px; border: 1px solid #cbd5e1; font-weight: 600;">[[耐药机制]]分布</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[T790M]]比例略低，[[靶外旁路]]较多</td>
                <td style="padding: 8px; border: 1px solid #cbd5e1;">[[T790M]]突变发生频率较高</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;">诊疗策略：2026年精准化选择</h2>
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        鉴于[[L858R突变]]在单药治疗中预后略逊于[[19-Del]]，2026年的临床策略更趋向于[[联合治疗]]与[[强效抑制]]：
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        <li style="margin-bottom: 12px;"><strong>[[三代TKI]]一线首选：</strong>根据[[FLAURA]]系列研究，[[奥希替尼]]或[[伏美替尼]]作为一线方案可显著改善[[L858R]]患者的[[无进展生存期]]。其优秀的[[血脑屏障]]通透性有效预防了该突变患者中位期后易发的[[脑转移]]。</li>
        <li style="margin-bottom: 12px;"><strong>[[A+T方案]]/[[A+L方案]]：</strong>对于[[极高风险]]的[[L858R]]患者，一线联用[[抗血管生成药物]]（如[[贝伐珠单抗]]或[[仑伐替尼]]）已被证实能产生更深度的[[肿瘤缓解]]，延缓[[耐药]]发生。</li>
        <li style="margin-bottom: 12px;"><strong>[[二代TKI]]的独特价值：</strong>[[ARCHER1050]]研究显示，[[达可替尼]]作为不可逆抑制剂，在[[L858R]]亚组中展现了非常稳健的[[总生存期]]（[[OS]]）优势。</li>
        <li style="margin-bottom: 12px;"><strong>[[共突变]]筛查：</strong>临床建议同时检测[[TP53]]、[[RB1]]等[[抑癌基因]]。若存在[[TP53]]共突变，[[L858R]]患者的治疗方案应更具侵袭性。</li>
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            <li style="margin-bottom: 8px;"><strong>[[19号外显子缺失]]：</strong>[[EGFR]]最常见的敏感突变，与[[L858R]]并称“[[黄金突变]]”。</li>
            <li style="margin-bottom: 8px;"><strong>[[敏感突变]]：</strong>指对[[第一代TKI]]表现出高度临床响应的一类[[EGFR]]变异。</li>
            <li style="margin-bottom: 8px;"><strong>[[点突变]]：</strong>DNA序列中单个[[核苷酸]]的改变，[[L858R]]是典型的[[错义点突变]]。</li>
            <li style="margin-bottom: 8px;"><strong>[[T790M]]：</strong>[[L858R]]患者在一代/二代药耐药后最主要的[[二次突变]]形式。</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>Mok TS, et al. (2009).</strong> <em>Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma.</em> <strong>[[The New England Journal of Medicine]]</strong>.[Academic Review]<br>
            <span style="color: #475569;">[权威点评]：IPASS研究里程碑式地证明了L858R等突变状态是决定TKI疗效的最关键因素。</span>
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            [2] <strong>Soria JC, et al. (2018).</strong> <em>Osimertinib in Untreated EGFR-Mutated Advanced NSCLC.</em> <strong>[[NEJM]]</strong>.<br>
            <span style="color: #475569;">[临床价值]：FLAURA研究确立了三代抑制剂作为L858R一线治疗的优效地位。</span>
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            [[L858R突变]] 诊疗生态 · 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;">关联靶点</td>
                <td style="padding: 10px 15px; color: #334155;">[[EGFR]]•[[HER2]]•[[TP53]]•[[MET]]•[[PIK3CA]]</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;">关联药物</td>
                <td style="padding: 10px 15px; color: #334155;">[[奥希替尼]]•[[达可替尼]]•[[吉非替尼]]•[[阿美替尼]]•[[贝伐珠单抗]]</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;">[[NCCN]]•[[CSCO]]•[[Novartis]]•[[AstraZeneca]]•[[辉瑞]]</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;">研究前沿</td>
                <td style="padding: 10px 15px; color: #334155;">[[L858R与TP53共突变治疗]]•[[新一代共价抑制剂开发]]•[[针对耐药后的ADC策略分析]]</td>
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