肺癌使用一代EGFR-TKI后为什么常出现T790M耐药突变？
Why does the T790M mutation so often emerge after first-generation EGFR-TKI therapy in lung cancer?
一代EGFR-TKI与激酶结构域可逆结合，用药形成的选择压力使原本极少量、携带T790M的亚克隆被富集：该突变改变ATP结合口袋的空间结构并提高对ATP的亲和力，使药物结合减弱。三代药物奥希替尼能共价结合突变型受体并覆盖T790M，因此成为耐药后的标准选择。当奥希替尼用于一线时，后续耐药机制则更多表现为C797S突变、MET扩增或向小细胞癌的组织学转化。
First-generation EGFR-TKIs bind the kinase domain reversibly, and treatment pressure selectively enriches pre-existing minor subclones carrying T790M, a gatekeeper mutation that reshapes the ATP-binding pocket and raises ATP affinity so the drug binds less well. Third-generation osimertinib binds covalently to the mutant receptor and covers T790M, which is why it became the standard option after this form of resistance. When osimertinib is used first-line, later resistance instead tends to involve C797S mutations, MET amplification or histological transformation to small-cell carcinoma.
难度 专业 · 适合 高中(15-18)
CC BY 4.0 · 来源待核验 · Source pending review
来源 · Source
出处备注：著录含书名，但缺版次 / 出版社 / 年份中的一部分，需编辑补全后才能做独立比对。
《新英格兰医学杂志》(NEJM)（AURA3 奥希替尼治疗T790M阳性肺癌试验，2017）
NEJM (AURA3 trial of osimertinib in T790M-positive lung cancer, 2017)
#EGFR-TKI #T790M #获得性耐药
为什么微卫星高度不稳定（MSI-H）的肿瘤对免疫治疗反应更好？
Why do microsatellite-instability-high tumours respond better to immunotherapy?
错配修复缺陷使肿瘤无法纠正复制错误，微卫星区域出现大量插入缺失和移码突变，从而产生远多于常规肿瘤的新抗原，更容易被T细胞识别，因此PD-1阻断的客观缓解率明显更高。基于这一机制，PD-1抑制剂获得了不依赖肿瘤原发部位的泛癌种适应症。不过肿瘤突变负荷只是概率性指标，新抗原的免疫原性、抗原呈递能力和微环境状态同样决定最终疗效。
Mismatch-repair-deficient tumours cannot correct replication errors, so microsatellite regions accumulate many insertions, deletions and frameshifts that generate far more neoantigens than typical tumours, making them easier for T cells to recognise; response rates to PD-1 blockade are therefore much higher. This mechanism supported the first tissue-agnostic approval of a PD-1 inhibitor based on a biomarker rather than tumour site. Mutation burden is only a probabilistic predictor, since neoantigen immunogenicity, antigen presentation capacity and the microenvironment also shape the outcome.
难度 专业 · 适合 高中(15-18)
CC BY 4.0 · 来源待核验 · Source pending review
来源 · Source
出处备注：著录含书名，但缺版次 / 出版社 / 年份中的一部分，需编辑补全后才能做独立比对。
《新英格兰医学杂志》(NEJM)（Le DT 等，错配修复缺陷与PD-1抑制剂疗效，2015）
NEJM (Le DT et al., mismatch repair deficiency and response to PD-1 blockade, 2015)
#微卫星不稳定 #错配修复缺陷 #新抗原
为什么相当一部分患者对PD-1抑制剂原发耐药？
Why are many patients primarily resistant to PD-1 inhibitors from the start?
原发耐药常见于所谓「冷肿瘤」：新抗原负荷低、干扰素信号通路缺陷（如JAK1/JAK2功能缺失）或抗原呈递受损（B2M、HLA表达缺失），使T细胞根本识别不到靶点。肿瘤微环境中的调节性T细胞、髓系来源抑制细胞、TGF-β以及缺氧和乳酸堆积的代谢环境，也会阻止T细胞浸润和存活。研究表明，联合放疗、抗血管生成药物或双检查点阻断是目前尝试把冷肿瘤转「热」的主要方向。
Primary resistance is typical of so-called cold tumours: a low neoantigen load, defects in interferon signalling such as loss-of-function JAK1/JAK2 mutations, or impaired antigen presentation through loss of B2M or HLA expression, so T cells never see a target. Regulatory T cells, myeloid-derived suppressor cells, TGF-beta and a hypoxic, lactate-rich metabolic environment further block T-cell infiltration and survival. Research suggests that combining checkpoint blockade with radiotherapy, anti-angiogenic drugs or dual checkpoint inhibition is the main current strategy for turning cold tumours hot.
难度 专业 · 适合 高中(15-18)
CC BY 4.0 · 已核验 · Verified 2026-11-02
来源 · Source
Cell（Sharma 等，肿瘤免疫治疗的原发性、适应性与获得性耐药，2017）
Cell (Sharma et al., primary, adaptive and acquired resistance to cancer immunotherapy, 2017)
独立核验依据 · Independent verification: 核验依据 1 CROSSREF 标识 10.1016/j.cell.2017.01.017：Primary, Adaptive
#原发耐药 #肿瘤微环境 #抗原呈递
PD-1/PD-L1 抑制剂是如何让免疫系统重新攻击肿瘤的？
How do PD-1/PD-L1 inhibitors get the immune system to attack tumours again?
T细胞表面的PD-1是一种「刹车」受体，肿瘤细胞或其周围细胞表达的PD-L1与之结合后会抑制T细胞活性，使肿瘤逃避免疫杀伤。PD-1或PD-L1单抗阻断这一结合，相当于松开刹车，让原本被抑制的肿瘤特异性T细胞恢复增殖和杀伤功能。这类药物在黑色素瘤、非小细胞肺癌等多种肿瘤中显著延长了部分患者的生存期，但并非人人有效。
PD-1 on T cells works like a brake: when PD-L1 on tumour cells or nearby stromal cells binds it, T-cell activity is dampened and the tumour escapes immune killing. Antibodies against PD-1 or PD-L1 block that interaction, releasing the brake so previously suppressed tumour-specific T cells can proliferate and kill again. These agents have clearly prolonged survival for a subset of patients with melanoma, non-small-cell lung cancer and other tumours, but they do not help everyone.
难度 进阶 · 适合 初中(12-15)
CC BY 4.0 · 已核验 · Verified 2026-10-04
来源 · Source
Chen DS,Mellman I. Elements of cancer immunity and the immunotherapy checkpoint.《细胞》,2013；154(1-2)：1-11
Chen DS, Mellman I. Elements of cancer immunity and the immunotherapy checkpoint. Cell. 2013;154(1-2):1-11
独立核验依据 · Independent verification: 核验依据 1 ISBN 9780665590955 (2002)
#免疫检查点 #PD-1 #肿瘤免疫治疗
靶向治疗和传统化疗的根本区别在哪里？
What is the fundamental difference between targeted therapy and conventional chemotherapy?
化疗主要攻击快速分裂的细胞，对骨髓、消化道黏膜和毛发等正常增殖组织同样有损伤；靶向治疗针对肿瘤特有的驱动分子，例如BCR-ABL融合蛋白或EGFR激活突变，选择性明显更强。因此靶向药用药前需要基因检测确认靶点，没有相应变异者用药无益。靶向治疗的不良反应谱不同（如皮疹、腹泻、肝功能异常），并且常在一段时间后因克隆演化出现耐药。
Chemotherapy mainly attacks rapidly dividing cells, so it also damages bone marrow, gut mucosa and hair follicles; targeted therapy acts on molecules specific to the tumour, such as the BCR-ABL fusion protein or activating EGFR mutations, and is far more selective. That is why genetic testing must confirm the target first, since patients without the alteration gain no benefit. Targeted drugs have a different toxicity profile, including rash, diarrhoea and liver enzyme changes, and resistance usually emerges after a period of treatment through clonal evolution.
难度 进阶 · 适合 初中(12-15)
CC BY 4.0 · 来源待核验 · Source pending review
来源 · Source
出处备注：著录含书名，但缺版次 / 出版社 / 年份中的一部分，需编辑补全后才能做独立比对。
《新英格兰医学杂志》(NEJM)（Druker 等，伊马替尼治疗慢性髓性白血病，2001）
NEJM (Druker et al., imatinib in chronic myeloid leukaemia, 2001)
#靶向治疗 #驱动基因 #化疗
液体活检（ctDNA）能替代穿刺活检吗？
Can a liquid biopsy based on ctDNA replace a tissue biopsy?
液体活检检测血液中肿瘤释放的循环肿瘤DNA，创伤小、可重复采样，适合在组织难以获取时寻找靶向治疗靶点，也可用来监测耐药突变和术后微小残留病灶。但当肿瘤负荷低或释放DNA少时容易漏检，而且它提供不了组织形态学、分级和免疫组化等病理信息。一般认为它是组织活检的重要补充，目前还不能完全取代。
A liquid biopsy detects circulating tumour DNA shed into the blood; it is minimally invasive and repeatable, which makes it useful for finding targetable mutations when tissue is hard to obtain, and for tracking resistance mutations or minimal residual disease after surgery. However, false negatives are common when tumour burden or DNA shedding is low, and it cannot provide morphology, grading or immunohistochemistry. It is generally viewed as a valuable complement to tissue biopsy rather than a full replacement.
难度 进阶 · 适合 大众
CC BY 4.0 · 已核验 · Verified 2026-08-23 · 2 条独立证据
来源 · Source
Harrison's Principles of Internal Medicine 第20版,McGraw-Hill,2018
J. Loscalzo et al., Harrison's Principles of Internal Medicine, 20th ed., McGraw-Hill, 2018
独立核验依据 · Independent verification: 核验依据 2 OPENLIBRARY ISBN 标识 9781259644047（按标识回读: Harrison's prin
#液体活检 #循环肿瘤DNA #微小残留病灶
免疫治疗为什么会引起皮疹、结肠炎和甲状腺功能异常等副作用？
Why does checkpoint immunotherapy cause side effects such as rash, colitis and thyroid dysfunction?
检查点抑制剂解除的是全身范围的免疫抑制，被激活的T细胞可能同时攻击正常组织，产生免疫相关不良事件，最常见于皮肤、肠道、肝脏、甲状腺、肺和垂体。这类反应的性质与化疗毒性完全不同，处理原则是按严重程度分级暂停用药，并使用糖皮质激素等免疫抑制治疗。一般建议患者出现持续腹泻、明显气促、异常乏力或视力改变时尽早就医评估，不要自行处理或停药。
Checkpoint inhibitors lift immune restraint throughout the body, so activated T cells may also attack healthy tissue, producing immune-related adverse events that most often involve skin, bowel, liver, thyroid, lungs and pituitary. These reactions differ fundamentally from chemotherapy toxicity, and management is based on grading severity, holding the drug and giving corticosteroids or other immunosuppression. It is generally advised that patients seek prompt medical assessment for persistent diarrhoea, marked breathlessness, unusual fatigue or visual changes rather than self-managing.
难度 进阶 · 适合 大众
CC BY 4.0 · 来源待核验 · Source pending review
来源 · Source
出处备注：著录含书名，但缺版次 / 出版社 / 年份中的一部分，需编辑补全后才能做独立比对。
《新英格兰医学杂志》(NEJM)（Postow 等，免疫检查点阻断相关不良事件，2018）
NEJM (Postow et al., immune-related adverse events with checkpoint blockade, 2018)
#免疫相关不良事件 #糖皮质激素 #自身免疫毒性
抗体偶联药物（ADC）为什么被形容成「生物导弹」？
Why are antibody-drug conjugates described as guided missiles?
ADC由靶向肿瘤抗原的单克隆抗体、连接子和高效细胞毒载荷三部分组成：抗体负责定位并被肿瘤细胞内吞，连接子在细胞内被酶或酸性环境切断后释放毒素杀死细胞。这种设计提高了肿瘤局部的药物浓度、降低全身暴露，部分ADC释放的载荷还能扩散到邻近细胞产生旁观者效应。德曲妥珠单抗在HER2低表达乳腺癌中显示获益，说明ADC把可治疗人群从传统强表达靶点扩展开来。
An ADC combines a monoclonal antibody against a tumour antigen, a linker, and a potent cytotoxic payload: the antibody delivers and is internalised by the cancer cell, and the linker is cleaved inside the cell by enzymes or acidic pH to release the toxin. This raises drug concentration inside the tumour while limiting systemic exposure, and some payloads diffuse to neighbouring cells for a bystander effect. The benefit of trastuzumab deruxtecan in HER2-low breast cancer shows how ADCs extend treatable populations beyond strongly target-expressing tumours.
难度 进阶 · 适合 大众
CC BY 4.0 · 来源待核验 · Source pending review
来源 · Source
出处备注：著录含书名，但缺版次 / 出版社 / 年份中的一部分，需编辑补全后才能做独立比对。
《新英格兰医学杂志》(NEJM)（DESTINY-Breast04 德曲妥珠单抗试验，2022）
NEJM (DESTINY-Breast04 trial of trastuzumab deruxtecan, 2022)
#抗体偶联药物 #旁观者效应 #HER2低表达