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SHR-A1811 (antibody-drug conjugate) in advanced HER2-mutant non-small cell lung cancer: a multicenter, open-label, phase 1/2 study. SHR-A1811(抗体药物结合物)治疗晚期HER2突变非小细胞肺癌:一项多中心、开放标签、1/2期研究。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 DOI: 10.1038/s41392-024-01897-y
Ziming Li, Zhengbo Song, Wei Hong, Nong Yang, Yongsheng Wang, Hong Jian, Zibin Liang, Sheng Hu, Min Peng, Yan Yu, Yan Wang, Zicong Jiao, Kaijing Zhao, Ke Song, You Li, Wei Shi, Shun Lu

A dose-escalation and expansion, phase 1/2 study (ClinicalTrials.gov, NCT04818333) was conducted to assess the novel antibody-drug conjugate SHR-A1811 in pretreated HER2-altered advanced non-small cell lung cancer (NSCLC). Here, we report results from the phase 1 portion. Patients who had previously failed or were intolerant to platinum-based chemotherapy were enrolled and received SHR-A1811 intravenously at doses of 3.2 to 8.0 mg/kg every 3 weeks. Dose escalation followed a Bayesian logistic regression model that included overdose control, with subsequent selection of tolerable levels for dose expansion. Overall, 63 patients were enrolled, including 43 receiving a recommended dose for expansion of 4.8 mg/kg. All patients had HER2-mutant disease. Dose-limiting toxicity occurred in one patient in the 8.0 mg/kg dose cohort. Grade ≥ 3 treatment-related adverse events occurred in 29 (46.0%) patients. One patient in the 6.4 mg/kg cohort died due to interstitial lung disease. As of April 11, 2023, the 4.8 mg/kg cohort showed an objective response rate of 41.9% (95% CI 27.0-57.9), and a disease control rate of 95.3% (95% CI 84.2-99.4). The median duration of response was 13.7 months, with 13 of 18 responses ongoing. The median progression-free survival was 8.4 months (95% CI 7.1-15.0). SHR-A1811 demonstrated favourable safety and clinically meaningful efficacy in pretreated advanced HER2-mutant NSCLC.

我们开展了一项剂量递增和扩大的1/2期研究(ClinicalTrials.gov,NCT04818333),以评估新型抗体药物共轭物SHR-A1811在HER2改变的晚期非小细胞肺癌(NSCLC)预处理中的疗效。在此,我们报告一期研究的结果。既往铂类化疗失败或不耐受的患者入组,静脉注射 SHR-A1811,剂量为 3.2 至 8.0 mg/kg,每 3 周一次。剂量升级遵循贝叶斯逻辑回归模型,其中包括过量控制,随后选择可耐受的剂量水平进行剂量扩增。共有 63 名患者入组,其中 43 人接受了 4.8 mg/kg 的推荐扩增剂量。所有患者均患有 HER2 突变疾病。8.0毫克/千克剂量组群中有一名患者出现了剂量限制性毒性。29名患者(46.0%)发生了≥3级的治疗相关不良事件。6.4毫克/千克剂量组群中有一名患者因间质性肺病死亡。截至2023年4月11日,4.8 mg/kg队列的客观应答率为41.9%(95% CI 27.0-57.9),疾病控制率为95.3%(95% CI 84.2-99.4)。中位应答持续时间为13.7个月,18例应答中有13例持续存在。无进展生存期中位数为 8.4 个月(95% CI 7.1-15.0)。SHR-A1811在预处理的晚期HER2突变NSCLC中表现出良好的安全性和有临床意义的疗效。
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引用次数: 0
Correction: A positive feedback inhibition of isocitrate dehydrogenase 3β on paired-box gene 6 promotes Alzheimer-like pathology. 更正:配对盒基因 6 上的异柠檬酸脱氢酶 3β 的正反馈抑制作用会促进阿尔茨海默氏症样病变。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-15 DOI: 10.1038/s41392-024-01904-2
Xin Wang, Qian Liu, Hai-Tao Yu, Jia-Zhao Xie, Jun-Ning Zhao, Zhi-Ting Fang, Min Qu, Yao Zhang, Ying Yang, Jian-Zhi Wang
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引用次数: 0
Correction: MELK is an oncogenic kinase essential for metastasis, mitotic progression, and programmed death in lung carcinoma. 更正:MELK 是一种致癌激酶,对肺癌的转移、有丝分裂进程和程序性死亡至关重要。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-13 DOI: 10.1038/s41392-024-01910-4
Qin Tang, Wan Li, Xiangjin Zheng, Liwen Ren, Jinyi Liu, Sha Li, Jinhua Wang, Guanhua Du
{"title":"Correction: MELK is an oncogenic kinase essential for metastasis, mitotic progression, and programmed death in lung carcinoma.","authors":"Qin Tang, Wan Li, Xiangjin Zheng, Liwen Ren, Jinyi Liu, Sha Li, Jinhua Wang, Guanhua Du","doi":"10.1038/s41392-024-01910-4","DOIUrl":"10.1038/s41392-024-01910-4","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":"186"},"PeriodicalIF":40.8,"publicationDate":"2024-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11246411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141604097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Synergistic induction of mitotic pyroptosis and tumor remission by inhibiting proteasome and WEE family kinases. 通过抑制蛋白酶体和 WEE 家族激酶,协同诱导有丝分裂期热休克和肿瘤缓解。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-12 DOI: 10.1038/s41392-024-01896-z
Zhan-Li Chen, Chen Xie, Wei Zeng, Rui-Qi Huang, Jin-E Yang, Jin-Yu Liu, Ya-Jing Chen, Shi-Mei Zhuang

Mitotic catastrophe (MC), which occurs under dysregulated mitosis, represents a fascinating tactic to specifically eradicate tumor cells. Whether pyroptosis can be a death form of MC remains unknown. Proteasome-mediated protein degradation is crucial for M-phase. Bortezomib (BTZ), which inhibits the 20S catalytic particle of proteasome, is approved to treat multiple myeloma and mantle cell lymphoma, but not solid tumors due to primary resistance. To date, whether and how proteasome inhibitor affected the fates of cells in M-phase remains unexplored. Here, we show that BTZ treatment, or silencing of PSMC5, a subunit of 19S regulatory particle of proteasome, causes G2- and M-phase arrest, multi-polar spindle formation, and consequent caspase-3/GSDME-mediated pyroptosis in M-phase (designated as mitotic pyroptosis). Further investigations reveal that inhibitor of WEE1/PKMYT1 (PD0166285), but not inhibitor of ATR, CHK1 or CHK2, abrogates the BTZ-induced G2-phase arrest, thus exacerbates the BTZ-induced mitotic arrest and pyroptosis. Combined BTZ and PD0166285 treatment (named BP-Combo) selectively kills various types of solid tumor cells, and significantly lessens the IC50 of both BTZ and PD0166285 compared to BTZ or PD0166285 monotreatment. Studies using various mouse models show that BP-Combo has much stronger inhibition on tumor growth and metastasis than BTZ or PD0166285 monotreatment, and no obvious toxicity is observed in BP-Combo-treated mice. These findings disclose the effect of proteasome inhibitors in inducing pyroptosis in M-phase, characterize pyroptosis as a new death form of mitotic catastrophe, and identify dual inhibition of proteasome and WEE family kinases as a promising anti-cancer strategy to selectively kill solid tumor cells.

有丝分裂灾难(MC)发生在有丝分裂失调的情况下,是一种专门消灭肿瘤细胞的迷人策略。有丝分裂灾难(MC)是有针对性地消灭肿瘤细胞的一种令人着迷的策略。蛋白酶体介导的蛋白质降解对M期至关重要。硼替佐米(BTZ)可抑制蛋白酶体的20S催化颗粒,被批准用于治疗多发性骨髓瘤和套细胞淋巴瘤,但由于原发性耐药性,不能用于实体瘤。迄今为止,蛋白酶体抑制剂是否以及如何影响M期细胞的命运仍未得到研究。在这里,我们发现BTZ处理或沉默蛋白酶体19S调控颗粒亚基PSMC5会导致G2期和M期停滞、多极纺锤体形成以及随之而来的由Caspase-3/GSDME介导的M期热凋亡(称为有丝分裂期热凋亡)。进一步的研究发现,WEE1/PKMYT1抑制剂(PD0166285),而非ATR、CHK1或CHK2抑制剂,能减弱BTZ诱导的G2期停滞,从而加剧BTZ诱导的有丝分裂停滞和裂解。BTZ 和 PD0166285 联合治疗(命名为 BP-Combo)可选择性地杀死各种类型的实体瘤细胞,与 BTZ 或 PD0166285 单药治疗相比,可显著降低 BTZ 和 PD0166285 的 IC50。利用各种小鼠模型进行的研究表明,BP-Combo 对肿瘤生长和转移的抑制作用远远强于 BTZ 或 PD0166285 单药治疗,而且 BP-Combo 治疗的小鼠没有观察到明显的毒性。这些发现揭示了蛋白酶体抑制剂在 M 期诱导热凋亡的作用,将热凋亡定性为有丝分裂灾难的一种新的死亡形式,并确定蛋白酶体和 WEE 家族激酶的双重抑制是选择性杀死实体瘤细胞的一种有前途的抗癌策略。
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引用次数: 0
Prosaposin hyperglycosylation: a novel tumor immune escape mechanism and implications for cancer immunotherapy. 前列腺素高糖基化:一种新型肿瘤免疫逃逸机制及其对癌症免疫疗法的影响
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-10 DOI: 10.1038/s41392-024-01877-2
Matthias Peipp, Diana Dudziak, Christian Kellner
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引用次数: 0
A deep learning-driven discovery of berberine derivatives as novel antibacterial against multidrug-resistant Helicobacter pylori. 深度学习驱动的小檗碱衍生物作为新型抗菌剂对抗耐多药幽门螺旋杆菌的发现。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-08 DOI: 10.1038/s41392-024-01895-0
Xixi Guo, Xiaosa Zhao, Xi Lu, Liping Zhao, Qingxuan Zeng, Fenbei Chen, Zhimeng Zhang, Mengyi Xu, Shijiao Feng, Tianyun Fan, Wei Wei, Xin Zhang, Jing Pang, Xuefu You, Danqing Song, Yanxiang Wang, Jiandong Jiang

Helicobacter pylori (H. pylori) is currently recognized as the primary carcinogenic pathogen associated with gastric tumorigenesis, and its high prevalence and resistance make it difficult to tackle. A graph neural network-based deep learning model, employing different training sets of 13,638 molecules for pre-training and fine-tuning, was aided in predicting and exploring novel molecules against H. pylori. A positively predicted novel berberine derivative 8 with 3,13-disubstituted alkene exhibited a potency against all tested drug-susceptible and resistant H. pylori strains with minimum inhibitory concentrations (MICs) of 0.25-0.5 μg/mL. Pharmacokinetic studies demonstrated an ideal gastric retention of 8, with the stomach concentration significantly higher than its MIC at 24 h post dose. Oral administration of 8 and omeprazole (OPZ) showed a comparable gastric bacterial reduction (2.2-log reduction) to the triple-therapy, namely OPZ + amoxicillin (AMX) + clarithromycin (CLA) without obvious disturbance on the intestinal flora. A combination of OPZ, AMX, CLA, and 8 could further decrease the bacteria load (2.8-log reduction). More importantly, the mono-therapy of 8 exhibited comparable eradication to both triple-therapy (OPZ + AMX + CLA) and quadruple-therapy (OPZ + AMX + CLA + bismuth citrate) groups. SecA and BamD, playing a major role in outer membrane protein (OMP) transport and assembling, were identified and verified as the direct targets of 8 by employing the chemoproteomics technique. In summary, by targeting the relatively conserved OMPs transport and assembling system, 8 has the potential to be developed as a novel anti-H. pylori candidate, especially for the eradication of drug-resistant strains.

幽门螺杆菌(Helicobacter pylori,H. pylori)是目前公认的与胃肿瘤发生相关的主要致癌病原体,其高发性和耐药性使其难以解决。基于图神经网络的深度学习模型采用了13638个分子的不同训练集进行预训练和微调,有助于预测和探索针对幽门螺杆菌的新型分子。预测结果表明,含有 3,13-二取代烯的新型小檗碱衍生物 8 对所有测试的药物敏感和耐药幽门螺杆菌菌株均有疗效,最低抑制浓度(MICs)为 0.25-0.5 μg/mL。药代动力学研究表明,8 号药物的胃保留率非常理想,服药后 24 小时的胃内浓度明显高于其 MIC 值。口服 8 和奥美拉唑(OPZ)与 OPZ + 阿莫西林(AMX)+ 克拉霉素(CLA)三联疗法相比,可减少胃内细菌(减少 2.2 个菌落),且对肠道菌群无明显干扰。OPZ、AMX、CLA 和 8 的组合可进一步减少细菌量(减少 2.8 个菌落)。更重要的是,8 的单一疗法与三联疗法(OPZ + AMX + CLA)和四联疗法(OPZ + AMX + CLA + 柠檬酸铋)组的根除效果相当。通过使用化学蛋白质组学技术,确定并验证了在外层膜蛋白(OMP)运输和组装中发挥重要作用的 SecA 和 BamD 是 8 的直接靶标。总之,通过靶向相对保守的外膜蛋白转运和组装系统,8 有可能被开发成一种新型的抗幽门螺杆菌候选药物,尤其是用于根除耐药菌株。
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引用次数: 0
Artificial intelligence meets body sense: task-driven neural networks reveal computational principles of the proprioceptive pathway. 人工智能与身体感知:任务驱动神经网络揭示本体感觉通路的计算原理。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-08 DOI: 10.1038/s41392-024-01870-9
Leonard E van Dyck, Frank Bremmer, Katharina Dobs
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引用次数: 0
Cancer stem cells: advances in knowledge and implications for cancer therapy. 癌症干细胞:知识的进步和对癌症治疗的影响。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-05 DOI: 10.1038/s41392-024-01851-y
Xianjing Chu, Wentao Tian, Jiaoyang Ning, Gang Xiao, Yunqi Zhou, Ziqi Wang, Zhuofan Zhai, Guilong Tanzhu, Jie Yang, Rongrong Zhou

Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.

癌症干细胞(CSCs)是肿瘤中的一小部分细胞,其特点是自我更新和持续增殖,导致肿瘤发生、转移并维持肿瘤的异质性。癌症仍然是全球重大的疾病负担。过去,手术、放疗和化疗是治疗癌症的主要方法。癌症治疗技术不断发展和进步,靶向治疗和免疫治疗的出现在一定程度上为患者提供了更多选择。然而,疗效和耐药性的局限性仍然不可避免。我们的综述首先简要介绍了调控 CSCs 的历史发现、原始假说和通路,如 WNT/β-Catenin、刺猬、Notch、NF-κB、JAK/STAT、TGF-β、PI3K/AKT、PPAR 通路及其交叉作用。我们的研究重点是 CSCs 在各种治疗结果和耐药性中的作用,包括治疗如何影响 CSCs 的含量及相关分子的改变、CSCs 介导的治疗耐药性,以及针对难治性、进展期或晚期肿瘤患者的 CSCs 的临床价值。总之,CSCs会影响疗效,而靶向CSCs的治疗方法仍难以确定。明确CSCs的调控机制和靶向生物标志物是目前的主流思路。
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引用次数: 0
Boosting liver regeneration: kinase inhibitor as a new tool to prevent liver failure. 促进肝脏再生:激酶抑制剂是预防肝衰竭的新工具。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-03 DOI: 10.1038/s41392-024-01879-0
Anna Sichler, Norbert Hüser, Klaus-Peter Janssen
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引用次数: 0
Semaphorin 3C (Sema3C) reshapes stromal microenvironment to promote hepatocellular carcinoma progression. Semaphorin 3C (Sema3C) 重塑基质微环境,促进肝细胞癌的进展。
IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-07-03 DOI: 10.1038/s41392-024-01887-0
Hao Peng, Meng Yang, Kun Feng, Qingpeng Lv, Yewei Zhang

More than 90% of hepatocellular carcinoma (HCC) cases develop in the presence of fibrosis or cirrhosis, making the tumor microenvironment (TME) of HCC distinctive due to the intricate interplay between cancer-associated fibroblasts (CAFs) and cancer stem cells (CSCs), which collectively regulate HCC progression. However, the mechanisms through which CSCs orchestrate the dynamics of the tumor stroma during HCC development remain elusive. Our study unveils a significant upregulation of Sema3C in fibrotic liver, HCC tissues, peripheral blood of HCC patients, as well as sorafenib-resistant tissues and cells, with its overexpression correlating with the acquisition of stemness properties in HCC. We further identify NRP1 and ITGB1 as pivotal functional receptors of Sema3C, activating downstream AKT/Gli1/c-Myc signaling pathways to bolster HCC self-renewal and tumor initiation. Additionally, HCC cells-derived Sema3C facilitated extracellular matrix (ECM) contraction and collagen deposition in vivo, while also promoting the proliferation and activation of hepatic stellate cells (HSCs). Mechanistically, Sema3C interacted with NRP1 and ITGB1 in HSCs, activating downstream NF-kB signaling, thereby stimulating the release of IL-6 and upregulating HMGCR expression, consequently enhancing cholesterol synthesis in HSCs. Furthermore, CAF-secreted TGF-β1 activates AP1 signaling to augment Sema3C expression in HCC cells, establishing a positive feedback loop that accelerates HCC progression. Notably, blockade of Sema3C effectively inhibits tumor growth and sensitizes HCC cells to sorafenib in vivo. In sum, our findings spotlight Sema3C as a novel biomarker facilitating the crosstalk between CSCs and stroma during hepatocarcinogenesis, thereby offering a promising avenue for enhancing treatment efficacy and overcoming drug resistance in HCC.

90%以上的肝细胞癌(HCC)病例是在纤维化或肝硬化的情况下发生的,这使得HCC的肿瘤微环境(TME)与众不同,因为癌症相关成纤维细胞(CAFs)和癌症干细胞(CSCs)之间存在着错综复杂的相互作用,它们共同调控着HCC的进展。然而,CSCs 在 HCC 发展过程中协调肿瘤基质动态的机制仍不明确。我们的研究揭示了Sema3C在纤维化肝脏、HCC组织、HCC患者外周血以及索拉非尼耐药组织和细胞中的显著上调,其过表达与HCC干性特性的获得相关。我们进一步发现,NRP1和ITGB1是Sema3C的关键功能受体,可激活下游的AKT/Gli1/c-Myc信号通路,从而促进HCC的自我更新和肿瘤的发生。此外,HCC细胞衍生的Sema3C有助于体内细胞外基质(ECM)的收缩和胶原沉积,同时还能促进肝星状细胞(HSCs)的增殖和活化。从机制上讲,Sema3C与造血干细胞中的NRP1和ITGB1相互作用,激活下游的NF-kB信号,从而刺激IL-6的释放并上调HMGCR的表达,进而促进造血干细胞中胆固醇的合成。此外,CAF 分泌的 TGF-β1 可激活 AP1 信号,从而增强 HCC 细胞中 Sema3C 的表达,建立一个正反馈回路,加速 HCC 的进展。值得注意的是,在体内阻断 Sema3C 能有效抑制肿瘤生长并使 HCC 细胞对索拉非尼敏感。总之,我们的研究结果表明,Sema3C是一种新型生物标记物,可在肝癌发生过程中促进癌细胞干细胞与基质之间的串联,从而为提高HCC的治疗效果和克服耐药性提供了一种前景广阔的途径。
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引用次数: 0
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Signal Transduction and Targeted Therapy
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