Signal Transduction and Targeted Therapy最新文献

{"title":"ACE-Breast-02: a randomized phase III trial of ARX788 versus lapatinib plus capecitabine for HER2-positive advanced breast cancer","authors":"Xichun Hu, Qingyuan Zhang, Leiping Wang, Jian Zhang, Quchang Ouyang, Xiaojia Wang, Wei Li, Weimin Xie, Zhongsheng Tong, Shusen Wang, Faliang Xu, Tao Sun, Wei Liu, Zhendong Chen, Jinsheng Wu, Ying Wang, Haixia Wang, Min Yan, Xinshuai Wang, Jingfen Wang, Feilin Cao, Yingying Du, Yongqiang Zhang, Lilin Chen, Ping Lu, Sanyuan Sun, Ruiwen Zhang, Aimin Zang, Xiuqing Nie, Yuan Lei","doi":"10.1038/s41392-025-02149-3","DOIUrl":"https://doi.org/10.1038/s41392-025-02149-3","url":null,"abstract":"<p>This phase III trial aimed to compare ARX788, a site-specific, construct-homogeneous antibody-drug conjugate, with lapatinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) who had progressed on one line of trastuzumab based regimen. Eligible patients were randomized (1:1) to receive ARX788 (1.5 mg/kg, IV, Q3W) or lapatinib plus capecitabine (LC: lapatinib 1250 mg QD; capecitabine 1000 mg/m² BID, days 1–14, Q3W) and stratified by prior chemotherapy lines (0-1 versus &gt;1) and visceral metastasis (yes versus no). The primary outcome was progression-free survival (PFS) assessed by a blinded independent central review (BICR). A total of 441 patients were randomly assigned to receive either ARX788 (<i>n</i> = 221) or LC (<i>n</i> = 220). The median PFS was 11.3 (95% confidence interval [CI], 8.4–13.8) months with ARX788 compared with 8.2 (95% CI, 6.9–8.7) months with LC, as per BICR (hazard ratio [HR] 0.64, <i>p</i> = 0.0006). Frequencies of treatment-related adverse events (TRAEs) of any grade were 98.6% and 99.1% for ARX788 and LC, respectively. Grade ≥3 TRAEs were 41.4% and 40.0%, respectively, the most common adverse events were blurred vision (12.3%), dry eye (9.1%), keratopathy (5.9%), and interstitial lung disease (ILD, 5.9%) with ARX788; hand-foot syndrome (18.1%) and hypokalemia (5.1%) with LC; all the hematological and gastrointestinal events of grade ≥3 with ARX788 were less than 3%. Six treatment-related deaths occurred, with three cases possibly related to ILD. ARX788 significantly improved PFS compared with LC in patients with HER2-positive ABC with a distinct toxicity profile, supporting it as a potential treatment option.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"1 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular principles underlying aggressive cancers","authors":"Ruth Nussinov, Bengi Ruken Yavuz, Hyunbum Jang","doi":"10.1038/s41392-025-02129-7","DOIUrl":"https://doi.org/10.1038/s41392-025-02129-7","url":null,"abstract":"<p>Aggressive tumors pose ultra-challenges to drug resistance. Anti-cancer treatments are often unsuccessful, and single-cell technologies to rein drug resistance mechanisms are still fruitless. The National Cancer Institute defines aggressive cancers at the tissue level, describing them as those that spread rapidly, despite severe treatment. At the molecular, foundational level, the quantitative biophysics discipline defines aggressive cancers as harboring a large number of (overexpressed, or mutated) crucial signaling proteins in major proliferation pathways populating their active conformations, primed for their signal transduction roles. This comprehensive review explores highly aggressive cancers on the foundational and cell signaling levels, focusing on the differences between highly aggressive cancers and the more treatable ones. It showcases aggressive tumors as harboring massive, cancer-promoting, catalysis-primed oncogenic proteins, especially through certain overexpression scenarios, as predisposed aggressive tumor candidates. Our examples narrate strong activation of ERK1/2, and other oncogenic proteins, through malfunctioning chromatin and crosslinked signaling, and how they activate multiple proliferation pathways. They show the increased cancer heterogeneity, plasticity, and drug resistance. Our review formulates the principles underlying cancer aggressiveness on the molecular level, discusses scenarios, and describes drug regimen (single drugs and drug combinations) for PDAC, NSCLC, CRC, HCC, breast and prostate cancers, glioblastoma, neuroblastoma, and leukemia as examples. All show overexpression scenarios of master transcription factors, transcription factors with gene fusions, copy number alterations, dysregulation of the epigenetic codes and epithelial-to-mesenchymal transitions in aggressive tumors, as well as high mutation loads of vital upstream signaling regulators, such as EGFR, c-MET, and K-Ras, befitting these principles.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"181 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143427125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successful treatment of transfusion-dependent β-thalassemia: multiple paths to reach potential cure","authors":"Michael Morgan, Axel Schambach","doi":"10.1038/s41392-025-02135-9","DOIUrl":"https://doi.org/10.1038/s41392-025-02135-9","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"80 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Full-length transcriptome atlas of gallbladder cancer reveals trastuzumab resistance conferred by ERBB2 alternative splicing.","authors":"Ziyi Wang, Li Gao, Ziheng Jia, Liguo Liu, Ao Gu, Zhaonan Liu, Qin Zhu, Yichen Zuo, Mingjie Yang, Shijia Wang, Jiyao Ma, Jingyun Zhang, Shimei Qiu, Zhizhen Li, Jinghan Wang, Dongxi Xiang, Fatao Liu, Rong Shao, Yanjing Li, Maolan Li, Wu Wei, Yingbin Liu","doi":"10.1038/s41392-025-02150-w","DOIUrl":"10.1038/s41392-025-02150-w","url":null,"abstract":"<p><p>Aberrant RNA alternative splicing in cancer generates varied novel isoforms and protein variants that facilitate cancer progression. Here, we employed the advanced long-read full-length transcriptome sequencing on gallbladder normal tissues, tumors, and cell lines to establish a comprehensive full-length gallbladder transcriptomic atlas. It is of note that receptor tyrosine kinases were one of the most dynamic components with highly variable transcript, with Erb-B2 receptor tyrosine kinase 2 (ERBB2) as a prime representative. A novel transcript, designated ERBB2 i14e, was identified for encoding a novel functional protein, and its protein expression was elevated in gallbladder cancer and strongly associated with worse prognosis. With the regulation of splicing factors ESRP1/2, ERBB2 i14e was alternatively spliced from intron 14 and the encoded i14e peptide was proved to facilitate the interaction with ERBB3 and downstream signaling activation of AKT. ERBB2 i14e was inducible and its expression attenuated anti-ERBB2 treatment efficacy in tumor xenografts. Further studies with patient derived xenografts models validated that ERBB2 i14e blockage with antisense oligonucleotide enhanced the tumor sensitivity to trastuzumab and its drug conjugates. Overall, this study provides a gallbladder specific long-read transcriptome profile and discovers a novel mechanism of trastuzumab resistance, thus ultimately devising strategies to improve trastuzumab therapy.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"54"},"PeriodicalIF":40.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415247","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}

{"title":"Pancreatic endocrine and exocrine signaling and crosstalk in physiological and pathological status.","authors":"Chenglin Hu, Yuan Chen, Xinpeng Yin, Ruiyuan Xu, Chenxue Yin, Chengcheng Wang, Yupei Zhao","doi":"10.1038/s41392-024-02098-3","DOIUrl":"10.1038/s41392-024-02098-3","url":null,"abstract":"<p><p>The pancreas, an organ with dual functions, regulates blood glucose levels through the endocrine system by secreting hormones such as insulin and glucagon. It also aids digestion through the exocrine system by secreting digestive enzymes. Complex interactions and signaling mechanisms between the endocrine and exocrine functions of the pancreas play a crucial role in maintaining metabolic homeostasis and overall health. Compelling evidence indicates direct and indirect crosstalk between the endocrine and exocrine parts, influencing the development of diseases affecting both. From a developmental perspective, the exocrine and endocrine parts share the same origin-the \"tip-trunk\" domain. In certain circumstances, pancreatic exocrine cells may transdifferentiate into endocrine-like cells, such as insulin-secreting cells. Additionally, several pancreatic diseases, including pancreatic cancer, pancreatitis, and diabetes, exhibit potential relevance to both endocrine and exocrine functions. Endocrine cells may communicate with exocrine cells directly through cytokines or indirectly by regulating the immune microenvironment. This crosstalk affects the onset and progression of these diseases. This review summarizes the history and milestones of findings related to the exocrine and endocrine pancreas, their embryonic development, phenotypic transformations, signaling roles in health and disease, the endocrine-exocrine crosstalk from the perspective of diseases, and potential therapeutic targets. Elucidating the regulatory mechanisms of pancreatic endocrine and exocrine signaling and provide novel insights for the understanding and treatment of diseases.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"39"},"PeriodicalIF":40.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414455","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}

{"title":"Restoring the supply lines: removing roadblocks to fatty acid uptake enhances T cell-driven cancer fight.","authors":"Jeremy G Baldwin, Caio R F Silveira, Luca Gattinoni","doi":"10.1038/s41392-025-02151-9","DOIUrl":"10.1038/s41392-025-02151-9","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":"53"},"PeriodicalIF":40.8,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143414816","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}

{"title":"IRE1α: a gatekeeper of chemotherapy-induced immunogenicity in triple-negative breast cancer","authors":"Nirmal Robinson, Ruhi Polara, Daniel Thomas","doi":"10.1038/s41392-025-02134-w","DOIUrl":"https://doi.org/10.1038/s41392-025-02134-w","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"56 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular insights and rational engineering of a compact CRISPR-Cas effector Cas12h1 with a broad-spectrum PAM","authors":"Weiwei Zheng, Hongyu Li, Mengxi Liu, Yuhang Wei, Bo Liu, Zekai Li, Chenyang Xiong, Shiqing Huang, Chunyi Hu, Songying Ouyang","doi":"10.1038/s41392-025-02147-5","DOIUrl":"https://doi.org/10.1038/s41392-025-02147-5","url":null,"abstract":"<p>Cas12h1 is a compact CRISPR-associated nuclease from functionally diverse type V CRISPR-Cas effectors and recognizes a purine-rich protospacer adjacent motif (PAM) distinct from that of other type V Cas effectors. Here, we report the nickase preference of Cas12h1, which predominantly cleaves the nontarget strand (NTS) of a double-stranded DNA (dsDNA) substrate. In addition, Cas12h1 acts as a nickase in human cells. We further determined the cryo-EM structures of Cas12h1 in the surveillance, R-loop formation, and interference states, revealing the molecular mechanisms involved in the crRNA maturation, target recognition, R-loop formation, nuclease activation and target degradation. Cas12h1 notably recognizes a broad 5’-DHR-3’ PAM (D is A, G, or T; H is A, C, or T; R is A or G) both in vitro and in human cells. In addition, Cas12h1 utilizes a distinct activation mechanism that the lid motif undergoes a “flexible to stable” transition to expose the catalytic site to the substrate. A high-fidelity nucleic acid detector, Cas12h1^hf, was developed through rational engineering, which distinguishes single-base mismatches and retains comparable on-target activities. Our results shed light on the molecular mechanisms underlying Cas12h1 nickase, improve the understanding of type V Cas effectors, and expand the CRISPR toolbox for genome editing and molecular diagnosis.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"10 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate and lactylation in cancer","authors":"Jie Chen, Ziyue Huang, Ya Chen, Hao Tian, Peiwei Chai, Yongning Shen, Yiran Yao, Shiqiong Xu, Shengfang Ge, Renbing Jia","doi":"10.1038/s41392-024-02082-x","DOIUrl":"https://doi.org/10.1038/s41392-024-02082-x","url":null,"abstract":"<p>Accumulated evidence has implicated the diverse and substantial influence of lactate on cellular differentiation and fate regulation in physiological and pathological settings, particularly in intricate conditions such as cancer. Specifically, lactate has been demonstrated to be pivotal in molding the tumor microenvironment (TME) through its effects on different cell populations. Within tumor cells, lactate impacts cell signaling pathways, augments the lactate shuttle process, boosts resistance to oxidative stress, and contributes to lactylation. In various cellular populations, the interplay between lactate and immune cells governs processes such as cell differentiation, immune response, immune surveillance, and treatment effectiveness. Furthermore, communication between lactate and stromal/endothelial cells supports basal membrane (BM) remodeling, epithelial-mesenchymal transitions (EMT), metabolic reprogramming, angiogenesis, and drug resistance. Focusing on lactate production and transport, specifically through lactate dehydrogenase (LDH) and monocarboxylate transporters (MCT), has shown promise in the treatment of cancer. Inhibitors targeting LDH and MCT act as both tumor suppressors and enhancers of immunotherapy, leading to a synergistic therapeutic effect when combined with immunotherapy. The review underscores the importance of lactate in tumor progression and provides valuable perspectives on potential therapeutic approaches that target the vulnerability of lactate metabolism, highlighting <i>the Heel of Achilles</i> for cancer treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"67 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143393103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uveal melanoma with a GNA11/GNAQ mutation secretes VEGF for systemic spread","authors":"Nguyễn Thị Thanh Nhàn, Sanjay Ganesh, Daniel E. Maidana, Michael J. Heiferman, Kaori H. Yamada","doi":"10.1038/s41392-025-02144-8","DOIUrl":"https://doi.org/10.1038/s41392-025-02144-8","url":null,"abstract":"","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"12 1","pages":""},"PeriodicalIF":39.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}