Drug Resistance Updates最新文献_第10页

A quiescence-like/TGF-β1-specific CRISPRi screen reveals drug uptake transporters as secondary targets of kinase inhibitors in AML 静止样/TGF-β1特异性CRISPRi筛选显示药物摄取转运蛋白是AML中激酶抑制剂的次要靶点

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-07-01 Epub Date: 2025-03-28 DOI: 10.1016/j.drup.2025.101242

Elahe Rahimian , Masoud Koochak , Sofia Traikov , Michael Schroeder , Silke Brilloff , Silvia Schäfer , Vida Kufrin , Sandra Küchler , Alexander Krüger , Peter Mirtschink , Gustavo Baretton , Evelin Schröck , Denis M. Schewe , Claudia R. Ball , Martin Bornhäuser , Hanno Glimm , Marius Bill , Alexander A. Wurm

Relapse in acute myeloid leukemia (AML) is driven by resistant subclones that survive chemotherapy. It is assumed that these resilient leukemic cells can modify their proliferative behavior by entering a quiescent-like state, similar to healthy hematopoietic stem cells (HSCs). These dormant cells can evade the effects of cytostatic drugs that primarily target actively dividing cells. Although quiescence has been extensively studied in healthy hematopoiesis and various solid cancers, its role in AML has remained unexplored.

In this study, we applied an HSC-derived quiescence-associated gene signature to an AML patient cohort and found it to be strongly correlated with poor prognosis and active TGF-β signaling. In vitro treatment with TGF-β1 induces a quiescence-like phenotype, resulting in a G0 shift and reduced sensitivity to cytarabine. To find potential therapeutic targets that prevent AML-associated quiescence and improve response to cytarabine, we conducted a comprehensive CRISPR interference (CRISPRi) screen combined with TGF-β1 stimulation. This approach identified TGFBR1 inhibitors, like vactosertib, as effective agents for preventing the G0 shift in AML cell models. However, pretreatment with vactosertib unexpectedly induced complete resistance to cytarabine. To elucidate the underlying mechanism, we performed a multi-faceted approach combining a second CRISPRi screen, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and in silico analysis. Our findings revealed that TGFBR1 inhibitors unintentionally target the nucleoside transporter SLC29A1 (ENT1), leading to reduced intracellular cytarabine levels. Importantly, we found that this drug interaction is not unique to TGFBR1 inhibitors, but extends to other clinically significant kinase inhibitors, such as the FLT3 inhibitor midostaurin. These findings may have important implications for optimizing combination therapies in AML treatment.

急性髓性白血病（AML）的复发是由化疗后存活的耐药亚克隆驱动的。据推测，这些有弹性的白血病细胞可以通过进入类似于健康造血干细胞（hsc）的静息状态来改变其增殖行为。这些休眠细胞可以逃避主要针对活跃分裂细胞的细胞抑制剂的作用。尽管在健康造血和各种实体癌中已广泛研究了静息，但其在AML中的作用仍未被探索。在这项研究中，我们将hsc衍生的静止相关基因标记应用于AML患者队列，发现它与不良预后和活跃的TGF-β信号传导密切相关。TGF-β1在体外处理可诱导静止样表型，导致G0移位，降低对阿糖胞苷的敏感性。为了寻找潜在的治疗靶点，防止aml相关的静止，提高对阿糖胞苷的反应，我们进行了综合的CRISPR干扰（CRISPRi）筛选，并结合TGF-β1刺激。该方法确定TGFBR1抑制剂，如vactosertib，是防止AML细胞模型中G0转移的有效药物。然而，vactosertib预处理出人意料地诱导了对阿糖胞苷的完全耐药。为了阐明潜在的机制，我们进行了多方面的方法，结合了第二次CRISPRi筛选、液相色谱-串联质谱（LC-MS/MS）和硅分析。我们的研究结果表明，TGFBR1抑制剂无意中靶向核苷转运体SLC29A1 (ENT1)，导致细胞内阿糖胞苷水平降低。重要的是，我们发现这种药物相互作用并不是TGFBR1抑制剂所独有的，而是延伸到其他临床重要的激酶抑制剂，如FLT3抑制剂midostoin。这些发现可能对优化AML治疗中的联合疗法具有重要意义。

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引用次数: 0

A novel platinum(IV) prodrug, gramine-Pt(IV) enhances chemoimmunotherapy by activating cGAS-STING and modulating TGF-β-MHC-I axis 一种新型铂（IV）前药gramine-Pt（IV）通过激活cGAS-STING和调节TGF-β-MHC-I轴来增强化学免疫治疗

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-07-01 Epub Date: 2025-05-11 DOI: 10.1016/j.drup.2025.101252

Bowen Ding , Xiaomeng Liu , Zhe Li , Xinru Xie , Jiaqi Li , Jiaqian Wang , Shouyi Li , Pengyu Wang , Yongjie Xie , Xiaoqing Ma , Hongwei Wang , Chengzhi Xie , Xin Qiao , Yumin Wang , Jingyuan Xu , Yukuan Feng , Jihui Hao

Platinum(II) (Pt(II)) drugs, such as cisplatin and oxaliplatin, played critical roles in cancer therapy; however, their efficacy is often limited by significant toxicity and the development of drug resistance. Recently, multi-target platinum(IV) (Pt(IV)) complexes, particularly those optimized with axial ligands, have emerged as promising alternatives enhancing tumor selectivity and drug stability. In this study, we synthesized a series of novel platinum(IV) prodrugs, gramine-platinum(IV), by incorporating gramine—a natural indole alkaloid that antagonizes TGF-β receptors I and II to inhibit the TGF-β signaling pathway—as an axial ligand. Among them, compound 8 (referred to as GP) was screened out to have the best antitumor activity. GP not only enhances the therapeutic efficacy of platinum(II) drugs but also targets TGF-β signaling. Our findings demonstrate that GP rapidly enters cells and preferentially accumulates in critical subcellular compartments, such as the nucleus and mitochondria, significantly amplifying its therapeutic impact. Notably, GP exhibits great tumor accumulation compared to cisplatin and oxaliplatin, with minimal uptake in normal tissues, highlighting its superior tumor specificity with reduced systemic toxicity. This unique characteristic enables GP to enhance therapeutic efficiency through multiple modalities, including strengthening DNA damage, reducing mitochondrial membrane potential, promoting apoptosis, and arresting cell cycle in the S phase. Moreover, GP activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling (cGAS-STING) pathway, enhancing antigen presentation and fostering robust anti-tumor immune responses. In mouse models of pancreatic and breast cancer, GP significantly inhibits tumor growth and triggers strong innate immune activation. By combining GP with anti-PD-1 therapy, immunotherapy-resistant tumors are rendered responsive, leading to a pronounced suppression of tumor growth. Overall, GP not only amplifies the DNA-damaging effects of platinum(II) drugs but also elicits durable immune responses, establishing itself as a promising chemo-immune-combined strategy for treating pancreatic and breast cancers.

铂（II）（Pt(II)）药物，如顺铂和奥沙利铂，在癌症治疗中起着关键作用；然而，它们的功效往往受到严重毒性和耐药性的限制。最近，多靶点铂（IV）（Pt(IV)）配合物，特别是那些轴向配体优化的配合物，已经成为增强肿瘤选择性和药物稳定性的有希望的替代品。在本研究中，我们合成了一系列新的铂（IV）前药，gramine-platinum(IV)，该药物以谷物（一种天然吲哚生物碱，可拮抗TGF-β受体I和II，抑制TGF-β信号通路）为轴向配体。其中，化合物8（简称GP）抗肿瘤活性最佳。GP不仅能提高铂类药物的疗效，还能靶向TGF-β信号通路。我们的研究结果表明，GP迅速进入细胞并优先积聚在关键的亚细胞区室，如细胞核和线粒体，显著增强了其治疗作用。值得注意的是，与顺铂和奥沙利铂相比，GP具有很大的肿瘤蓄积，在正常组织中摄取很少，突出了其优越的肿瘤特异性和降低的全身毒性。这种独特的特性使GP能够通过多种方式提高治疗效率，包括加强DNA损伤，降低线粒体膜电位，促进细胞凋亡，并在S期阻滞细胞周期。此外，GP激活环GMP-AMP合成酶(cGAS)-干扰素基因（STING）信号通路（cGAS-STING），增强抗原呈递并促进强大的抗肿瘤免疫反应。在胰腺癌和乳腺癌小鼠模型中，GP显著抑制肿瘤生长并触发强先天免疫激活。通过将GP与抗pd -1治疗相结合，免疫治疗抵抗性肿瘤呈现反应性，导致肿瘤生长明显受到抑制。总的来说，GP不仅增强了铂（II）药物的dna损伤作用，而且还引发了持久的免疫反应，使其成为治疗胰腺癌和乳腺癌的一种有前途的化学-免疫联合策略。

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引用次数: 0

Profiling the landscape of carbapenem resistance and hypervirulence in Klebsiella pneumoniae: A global epidemiological analysis of the plasmidome 分析肺炎克雷伯菌碳青霉烯耐药和高毒力的情况：质粒的全球流行病学分析

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-07-01 Epub Date: 2025-05-20 DOI: 10.1016/j.drup.2025.101254

Heng Heng , Ruanyang Sun , Xuemei Yang , Lianwei Ye , Kaichao Chen , Jun Li , Edward Wai-Chi Chan , Rungsheng Li , Rong Zhang , Sheng Chen

The emergence and spread of carbapenem resistance (CR) and hypervirulence (hv) in Klebsiella pneumoniae represent a growing global health threat. Plasmids play an important role in the dissemination of these traits; however, the plasmidome of draft genomes of a large number of K. pneumoniae has not been analyzed so far. To recover K. pneumoniae plasmids, OMAP-KP was developed, achieving a recall rate of 85.27 % for plasmids exceeding 10,000 bp in length from draft genomes. From a global collection of 69,969 K. pneumoniae genomes, we identified 226,110 plasmids, providing the most comprehensive profiling of the K. pneumoniae plasmidome to date. The study recovered 12,790 KPC-encoding plasmids, 6214 NDM-encoding plasmids, and 6843 hv plasmids. Plasmid KPC PC_392 was found to be associated with ST11 K. pneumoniae in China, featuring the klcA within the genetic context around bla_KPC. NDM plasmids exhibited a widespread distribution, and stabilization began before 2015. There was an increased prevalence of bla_NDM-5 with the qnrS1 gene compared to bla_NDM-1 after 2020. The frequent convergence of CR and hv plasmid pairs was observed in different STs: hv PC_499 with KPC PC_362 (ST11) and OXA PC_7078 (ST15), and hv PC_394 with OXA PC_7078 (ST2096) and OXA PC_804 (ST383), suggesting clone transmission of K. pneumoniae carrying CR-hv plasmid pairs. Alarmingly, PC_394 can encode both hv loci and CR genes, with an increasing prevalence detected from the public database from North America and Europe & Central Asia after 2019, which might result from the change of isolation or treatment strategy, or potentially from the ongoing spread of plasmids that have not been detected in other areas. This observed pattern coincides with the period of the COVID-19 pandemic needs further investigation. This study highlights the potential to integrate plasmid-level analysis into genome surveillance projects. The plasmidome reference and identification approach can track the emergence and convergence of CR and hv PCs in the evolution and transmission of K. pneumoniae, paving the way for more effective interventions to protect public health.

肺炎克雷伯菌碳青霉烯耐药（CR）和高毒力（hv）的出现和传播代表着日益严重的全球健康威胁。质粒在这些性状的传播中起着重要作用；然而，大量肺炎克雷伯菌草稿基因组的质粒尚未得到分析。为了回收肺炎克雷伯菌质粒，开发了OMAP-KP，对长度超过10,000 bp的质粒从草稿基因组中回收率为85.27 %。从69,969个全球收藏 K。我们鉴定了226,110个质粒，提供了迄今为止最全面的肺炎克雷伯菌质粒谱。该研究回收了12790个编码kpc的质粒，6214个编码ndm的质粒和6843个hv质粒。在中国发现质粒KPC PC_392与ST11肺炎克雷伯菌相关，其特征是在blaKPC周围的遗传背景下存在klcA。NDM质粒分布广泛，并在2015年之前开始稳定。2020年后，与blaNDM-1相比，携带qnrS1基因的blaNDM-5的患病率增加。在不同的STs中观察到CR和hv质粒对的频繁收敛：hv PC_499与KPC PC_362 （ST11）和OXA PC_7078 (ST15)， hv PC_394与OXA PC_7078 （ST2096）和OXA PC_804 (ST383)，提示肺炎克雷伯菌携带CR-hv质粒对进行了克隆传播。令人担忧的是，PC_394可以同时编码hv基因座和CR基因，在北美和欧洲的公共数据库中检测到的流行率越来越高。这可能是由于隔离或治疗策略的改变，也可能是由于在其他地区未发现的质粒正在传播。这一观察到的模式与COVID-19大流行期间相吻合，需要进一步调查。这项研究强调了将质粒水平分析整合到基因组监测项目中的潜力。质粒参考和鉴定方法可以追踪肺炎克雷伯菌进化和传播过程中CR和hv pc的出现和趋同，为更有效的干预措施铺平道路，保护公众健康。

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引用次数: 0

Overcoming cancer therapy resistance: From drug innovation to therapeutics 克服癌症治疗耐药性：从药物创新到治疗方法

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-07-01 Epub Date: 2025-03-08 DOI: 10.1016/j.drup.2025.101229

Jin-Rui Wei , Meng-Yi Lu , Tian-Hua Wei , Joshua S. Fleishman , Hui Yu , Xiao-Li Chen , Xiang-Tu Kong , Shan-Liang Sun , Nian-Guang Li , Ye Yang , Hai-Wen Ni

One of the major limitations of cancer therapy is the emergence of drug resistance. This review amis to provide a focused analysis of the multifactorial mechanisms underlying therapy resistance,with an emphasis on actionable insights for developing novel therapeutic strategies. It concisely outlines key factors contributing to therapy resistance, including drug delivery barriers, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer heterogeneity, tumor microenvironment (TME), genetic mutations, and alterlations in gene expression. Additionally, we explore how tumors evade targeted therapies through pathway-specific mechanisms that restore disrupted signaling pathways. The review critically evaluates innovative strategies designed to sensitize resistant tumor cells, such as targeted protein dedgradation, antibody-drug conjugates, structure-based drug design, allosteric drugs, multitarget drugs, nanomedicine and others We also highlight the importance of understanding the pharmacological actions of these agents and their integration into treatment regimens. By synthesizing current knowledge and identifying gaps in our understanding, this review aims to guide future research and improve patient outcomes in cancer therapy.

癌症治疗的主要限制之一是耐药性的出现。这篇综述旨在集中分析治疗耐药的多因素机制，重点是为开发新的治疗策略提供可行的见解。它简明扼要地概述了导致治疗耐药的关键因素，包括药物递送障碍、癌症干细胞（CSCs）、上皮-间质转化（EMT）、癌症异质性、肿瘤微环境（TME）、基因突变和基因表达改变。此外，我们探索肿瘤如何通过恢复中断的信号通路的途径特异性机制逃避靶向治疗。这篇综述批判性地评估了旨在使耐药肿瘤细胞增敏的创新策略，如靶向蛋白降解、抗体-药物偶联物、基于结构的药物设计、变构药物、多靶点药物、纳米药物等。我们还强调了了解这些药物的药理作用及其与治疗方案结合的重要性。通过综合目前的知识和识别我们的理解差距，这篇综述旨在指导未来的研究和改善癌症治疗的患者结果。

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引用次数: 0

Aging and senescence: Key players in brain tumor progression and drug resistance 衰老和衰老：脑肿瘤进展和耐药性的关键因素

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-07-01 Epub Date: 2025-03-08 DOI: 10.1016/j.drup.2025.101228

Chao Zhang , Neha , Jiaqi Zhang , Prashant , Xiaodie Li , Sarad Kumar Mishra , Joshua Fleishman , Suhel Parvez , Saurabh Kumar Jha , Min Huang

Aging plays a critical role in the development, progression, and therapeutic challenges associated with brain tumors, particularly glioblastomas (GBM). As the population ages, the incidence of brain tumors, including GBM, increases, with aging emerging as a significant prognostic factor influencing survival outcomes. This review examines the molecular mechanisms linking aging and brain tumor progression, with a specific focus on glioblastomas. We explore how age-related genetic mutations, alterations in cellular pathways, and changes in the tumor microenvironment (TME) contribute to tumorigenesis and treatment resistance. Furthermore, we highlight the impact of key signaling pathways, such as the PI3K/AKT/mTOR, p53, and EGFR/PTEN, which are frequently dysregulated in both aging and brain tumors. Despite the growing recognition of aging as a critical factor in brain tumor biology, therapeutic strategies for elderly patients remain poorly defined, often due to underrepresentation in clinical trials and the complex interplay of comorbidities and treatment side effects. The review also discusses emerging therapeutic approaches, including targeted therapies and immunotherapies, which offer promise for improving treatment outcomes by addressing age-related molecular changes. Finally, we emphasize the importance of personalized treatment strategies and the need for further research to better understand the biological mechanisms underlying the aging-brain tumor relationship, ultimately aiming to enhance clinical management and patient quality of life.

衰老在脑肿瘤，特别是胶质母细胞瘤（GBM）的发生、进展和治疗挑战中起着关键作用。随着人口老龄化，脑肿瘤（包括GBM）的发病率增加，老龄化成为影响生存结果的重要预后因素。这篇综述探讨了衰老和脑肿瘤进展的分子机制，特别关注胶质母细胞瘤。我们探讨了与年龄相关的基因突变、细胞通路的改变和肿瘤微环境（TME）的变化如何促进肿瘤的发生和治疗耐药性。此外，我们强调了关键信号通路的影响，如PI3K/AKT/mTOR， p53和EGFR/PTEN，这些信号通路在衰老和脑肿瘤中经常失调。尽管人们越来越认识到衰老是脑肿瘤生物学中的一个关键因素，但老年患者的治疗策略仍然不明确，这通常是由于临床试验中代表性不足以及合共病和治疗副作用的复杂相互作用。这篇综述还讨论了新兴的治疗方法，包括靶向治疗和免疫治疗，它们有望通过解决与年龄相关的分子变化来改善治疗效果。最后，我们强调个性化治疗策略的重要性和进一步研究的必要性，以更好地了解衰老与脑肿瘤关系的生物学机制，最终旨在提高临床管理和患者的生活质量。

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引用次数: 0

Targeting NAT10 attenuates homologous recombination via destabilizing DNA:RNA hybrids and overcomes PARP inhibitor resistance in cancers 靶向NAT10通过破坏DNA:RNA杂交体减弱同源重组，并克服癌症中PARP抑制剂的耐药性

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-07-01 Epub Date: 2025-03-22 DOI: 10.1016/j.drup.2025.101241

Zhu Xu , Mingming Zhu , Longpo Geng , Jun Zhang , Jing Xia , Qiang Wang , Hongda An , Anliang Xia , Yuanyuan Yu , Shihan Liu , Junjie Tong , Wei-Guo Zhu , Yiyang Jiang , Beicheng Sun

Aims

RNA metabolism has been extensively studied in DNA double-strand break (DSB) repair. The RNA acetyltransferase N-acetyltransferase 10 (NAT10)-mediated N4-acetylcytidine (ac4C) modification in DSB repair remains largely elusive. In this study, we aim to decipher the role for ac4C modification by NAT10 in DSB repair in hepatocellular carcinoma (HCC).

Methods

Laser micro-irradiation and chromatin immunoprecipitation (ChIP) were used to assess the accumulation of ac4C modification and NAT10 at DSB sites. Cryo-electron microscopy (cryo-EM) was used to determine the structures of NAT10 in complex with its inhibitor, remodelin. Hepatocyte-specific deletion of NAT10 mouse models were adopted to detect the effects of NAT10 on HCC progression. Subcutaneous xenograft, human HCC organoid and patient-derived xenograft (PDX) model were exploited to determine the therapy efficiency of the combination of a poly (ADP-ribose) polymerase 1 (PARP1) inhibitor (PARPi) and remodelin.

Results

NAT10 promptly accumulates at DSB sites, where it executes ac4C modification on RNAs at DNA:RNA hybrids dependent on PARP1. This in turn enhances the stability of DNA:RNA hybrids and promotes homologous recombination (HR) repair. The ablation of NAT10 curtails HCC progression. Furthermore, the cryo-EM yields a remarkable 2.9 angstroms resolution structure of NAT10-remodelin, showcasing a C2 symmetric architecture. Remodelin treatment significantly enhanced the sensitivity of HCC cells to a PARPi and targeting NAT10 also restored sensitivity to a PARPi in ovarian and breast cancer cells that had developed resistance.

Conclusion

Our study elucidated the mechanism of NAT10-mediated ac4C modification in DSB repair, revealing that targeting NAT10 confers synthetic lethality to PARP inhibition in HCC. Our findings suggest that co-inhibition of NAT10 and PARP1 is an effective novel therapeutic strategy for patients with HCC and have the potential to overcome PARPi resistance.

aimrna代谢在DNA双链断裂（DSB）修复过程中得到了广泛的研究。RNA乙酰转移酶n -乙酰转移酶10 （NAT10）介导的n4 -乙酰胞苷（ac4C）修饰在DSB修复中的作用尚不明确。在这项研究中，我们旨在破译NAT10修饰ac4C在肝细胞癌（HCC） DSB修复中的作用。方法采用激光微照射法和染色质免疫沉淀法（ChIP）检测ac4C修饰和NAT10在DSB位点的积累情况。低温电子显微镜（cryo-EM）测定了NAT10及其抑制剂重塑蛋白复合物的结构。采用肝细胞特异性缺失NAT10小鼠模型检测NAT10对HCC进展的影响。利用皮下异种移植物、人类肝癌类器官和患者来源的异种移植物（PDX）模型来确定聚（adp -核糖）聚合酶1 （PARP1）抑制剂（PARPi）和重塑蛋白联合使用的治疗效果。结果tsnat10在DSB位点迅速积累，在此对依赖PARP1的DNA:RNA杂交体的RNA进行ac4C修饰。这反过来又增强了DNA:RNA杂交体的稳定性，并促进同源重组（HR）修复。消融NAT10可抑制HCC进展。此外，低温电镜（cryo-EM）显示出2.9埃分辨率的nat10 -重塑蛋白结构，显示出C2对称结构。重塑蛋白治疗显著增强了HCC细胞对PARPi的敏感性，靶向NAT10也恢复了已产生耐药性的卵巢癌和乳腺癌细胞对PARPi的敏感性。结论我们的研究阐明了NAT10介导的ac4C修饰在DSB修复中的机制，揭示了靶向NAT10对肝癌中PARP抑制具有合成致死性。我们的研究结果表明，共同抑制NAT10和PARP1是HCC患者有效的新治疗策略，并有可能克服PARPi耐药性。

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引用次数: 0

Targeting TRAP1-dependent metabolic reprogramming to overcome doxorubicin resistance in quiescent breast cancer 靶向trap1依赖性代谢重编程克服静止型乳腺癌阿霉素耐药

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-07-01 Epub Date: 2025-03-03 DOI: 10.1016/j.drup.2025.101226

Muhammad Zubair Saleem , Ruyi Huang , Yingying Huang , Xin Guo , Yang Liu , Miao Gao , Yinjuan Fan , Zhe-Sheng Chen , Zun-Fu Ke , Shengnan Ye , Jianhua Xu

Aims

TRAP1 is involved in metabolic reprogramming and promotes drug resistance. We aimed to explore whether a novel HSP90 inhibitor, C210, overcomes doxorubicin (DOX) resistance of quiescent breast cancer cells by targeting TRAP1.

Methods

Breast cancer cells were induced to quiescence by hypoxia and low glucose. The relationship of cell metabolism with HSP90 and TRAP1 was investigated by Western blotting, ECAR, OCR, mitochondrial complex activity, and proteomic analysis. The targets of C210 and their functions were analyzed by SPR and immunoprecipitation. The antitumor effect in vivo was investigated with mouse tumor model.

Results

In hypoxia and glucose deprivation, breast cancer cells exhibited elevated TRAP1 and an OXPHOS-enhanced quiescent phenotype. These cells were highly resistant to DOX but more sensitive to C210. C210 disrupted TRAP1's interaction with OXPHOS-associated client proteins, prompting proteasome-dependent degradation of these proteins, thereby reducing OCR, mitochondrial ATP production and resulting in selective elimination of the quiescent cancer cells by inducing mitochondrial apoptosis which could be reversed by exogenous ATP. Moreover, C210 targeted glycolytic, amino acid, and β-oxidation-associated proteome. C210 demonstrated promising in vivo anticancer efficacy which was particularly related to OXPHOS inhibition.

Conclusions

C210 eliminates DOX-resistant quiescent breast cancer cells by targeting TRAP1-dependent bioenergetics.

AimsTRAP1参与代谢重编程并促进耐药。我们的目的是探索一种新的HSP90抑制剂C210是否通过靶向TRAP1来克服静止乳腺癌细胞的多柔比星（DOX）耐药性。方法采用低氧、低糖诱导乳腺癌细胞静息。通过Western blotting、ECAR、OCR、线粒体复合物活性和蛋白质组学分析研究细胞代谢与HSP90和TRAP1的关系。通过SPR和免疫沉淀分析C210的靶点及其功能。采用小鼠肿瘤模型研究其体内抗肿瘤作用。结果在缺氧和葡萄糖剥夺的情况下，乳腺癌细胞表现出TRAP1升高和oxphos增强的静止表型。这些细胞对DOX高度耐药，但对C210更敏感。C210破坏了TRAP1与oxphos相关客户蛋白的相互作用，促使蛋白酶体依赖性降解这些蛋白，从而减少OCR和线粒体ATP的产生，并通过诱导线粒体凋亡（可被外源ATP逆转）选择性消除静止癌细胞。此外，C210靶向糖酵解、氨基酸和β-氧化相关蛋白质组。C210在体内表现出良好的抗癌作用，特别是与抑制OXPHOS有关。结论sc210通过靶向trap1依赖的生物能量学来消除dox耐药的静止乳腺癌细胞。

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引用次数: 0

DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in hepatocellular carcinoma DTX2通过抑制肝细胞癌中hsd17b4依赖性过氧化物酶体β-氧化的二十二碳六烯酸生物合成，减轻lenvatinib诱导的铁凋亡

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-07-01 Epub Date: 2025-02-28 DOI: 10.1016/j.drup.2025.101224

Zhongyan Zhang , Qi Zhou , Zhenchong Li , Fuxin Huang , Ke Mo , Cheng Shen , Xing Niu , Baohua Hou , Chuanzhao Zhang , Shanzhou Huang

Aims

Emerging resistance to Lenvatinib, which is used as a first-line agent for the treatment of advanced hepatocellular carcinoma (HCC), is still a concern. The aim of this study was to determine core factors of Lenvatinib resistance (LR) and their underlying molecular mechanisms.

Methods

CRISPR screening in HCC cells was conducted, which identified E3 ubiquitin ligase deltex 2 (DTX2) as a core LR-related gene. In vivo and in vitro models were used to clarify the function of DTX2 on LR and ferroptosis. The upstream regulators and downstream effectors of DTX2 were identified, revealing its complex regulatory network.

Results

DTX2 promoted anti-ferroptosis in LR HCC cells via downregulating the peroxisomal β-oxidation enzyme HSD17B4. DTX2 induced the ubiquitination-mediated degradation of HSD17B4, resulting in lipid metabolism changes that were associated mainly with docosahexaenoic acid (DHA)-containing PUFAs. Notably, DHA supplements could reverse DTX2-induced anti-ferroptosis and LR. Mechanistically, we uncovered that DTX2 ubiquitinated the HSD17B4 SCP structural domain through its RING structural domain and ubiquitinated the K645 site. The upregulation of DTX2 expression was mediated by JAK2-STAT3 pathway activation. The aberrant activation of STAT3 in acquired LR promoted DTX2 transcription and negatively regulated peroxisomal β-oxidation via K48-ubiquitinated HSD17B4 and decreased DHA-phospholipids levels, leading to the suppression of Lenvatinib-induced ferroptosis in HCC.

Conclusions

Our findings suggest that DTX2 attenuates Lenvatinib-induced ferroptosis by inhibiting DHA biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in HCC. The combination of DHA with Lenvatinib could be a promising therapeutic strategy for patients with LR HCC.

Lenvatinib作为治疗晚期肝细胞癌（HCC）的一线药物，对Lenvatinib的新耐药性仍然是一个问题。本研究旨在确定Lenvatinib耐药（LR）的核心因素及其潜在的分子机制。方法对HCC细胞进行crispr筛选，发现E3泛素连接酶deltex 2 （DTX2）为核心lr相关基因。采用体内和体外模型阐明DTX2对LR和铁下垂的作用。确定了DTX2的上游调控因子和下游效应因子，揭示了其复杂的调控网络。结果dtx2通过下调过氧化物酶体β-氧化酶HSD17B4促进LR肝癌细胞抗铁凋亡。DTX2诱导了泛素化介导的HSD17B4降解，导致脂质代谢的变化，这种变化主要与含二十二碳六烯酸（DHA）的PUFAs有关。值得注意的是，DHA补充剂可以逆转dtx2诱导的抗铁下垂和LR。在机制上，我们发现DTX2通过其RING结构域泛素化HSD17B4的SCP结构域，并泛素化K645位点。DTX2表达上调是通过激活JAK2-STAT3通路介导的。获得性LR中STAT3的异常激活可促进DTX2转录，并通过k48泛素化HSD17B4负调控过氧化物酶体β-氧化，降低dha磷脂水平，从而抑制lenvatinib诱导的HCC铁凋亡。结论DTX2通过hsd17b4依赖性过氧化物酶体β-氧化抑制DHA在HCC中的生物合成，从而减轻lenvatinib诱导的铁凋亡。DHA联合Lenvatinib可能是LR HCC患者的一种有希望的治疗策略。

{"title":"DTX2 attenuates Lenvatinib-induced ferroptosis by suppressing docosahexaenoic acid biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in hepatocellular carcinoma","authors":"Zhongyan Zhang , Qi Zhou , Zhenchong Li , Fuxin Huang , Ke Mo , Cheng Shen , Xing Niu , Baohua Hou , Chuanzhao Zhang , Shanzhou Huang","doi":"10.1016/j.drup.2025.101224","DOIUrl":"10.1016/j.drup.2025.101224","url":null,"abstract":"<div><h3>Aims</h3><div>Emerging resistance to Lenvatinib, which is used as a first-line agent for the treatment of advanced hepatocellular carcinoma (HCC), is still a concern. The aim of this study was to determine core factors of Lenvatinib resistance (LR) and their underlying molecular mechanisms.</div></div><div><h3>Methods</h3><div>CRISPR screening in HCC cells was conducted, which identified E3 ubiquitin ligase deltex 2 (DTX2) as a core LR-related gene. <em>In vivo</em> and <em>in vitro</em> models were used to clarify the function of DTX2 on LR and ferroptosis. The upstream regulators and downstream effectors of DTX2 were identified, revealing its complex regulatory network.</div></div><div><h3>Results</h3><div>DTX2 promoted anti-ferroptosis in LR HCC cells via downregulating the peroxisomal β-oxidation enzyme HSD17B4. DTX2 induced the ubiquitination-mediated degradation of HSD17B4, resulting in lipid metabolism changes that were associated mainly with docosahexaenoic acid (DHA)-containing PUFAs. Notably, DHA supplements could reverse DTX2-induced anti-ferroptosis and LR. Mechanistically, we uncovered that DTX2 ubiquitinated the HSD17B4 SCP structural domain through its RING structural domain and ubiquitinated the K645 site. The upregulation of DTX2 expression was mediated by JAK2-STAT3 pathway activation. The aberrant activation of STAT3 in acquired LR promoted DTX2 transcription and negatively regulated peroxisomal β-oxidation via K48-ubiquitinated HSD17B4 and decreased DHA-phospholipids levels, leading to the suppression of Lenvatinib-induced ferroptosis in HCC.</div></div><div><h3>Conclusions</h3><div>Our findings suggest that DTX2 attenuates Lenvatinib-induced ferroptosis by inhibiting DHA biosynthesis through HSD17B4-dependent peroxisomal β-oxidation in HCC. The combination of DHA with Lenvatinib could be a promising therapeutic strategy for patients with LR HCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"81 ","pages":"Article 101224"},"PeriodicalIF":15.8,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143577501","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}

引用次数: 0

Corrigendum to “Opposite evolution of pathogenicity driven by in vivo wzc and wcaJ mutations in ST11-KL64 carbapenem-resistant Klebsiella pneumoniae” [Drug Resist. Updat. 66 (2023) 100891] “ST11-KL64耐碳青霉烯肺炎克雷伯菌体内wzc和wcaJ突变驱动的致病性相反进化”的勘误表[耐药]。更新。66 (2023)100891]

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-07-01 Epub Date: 2025-04-30 DOI: 10.1016/j.drup.2025.101244

Jintao He , Qiucheng Shi , Zhifu Chen , Wang Zhang , Peng Lan , Qingye Xu , Huangdu Hu , Qiong Chen , Jianzhong Fan , Yan Jiang , Belinda Loh , Sebastian Leptihn , Quanming Zou , Jinyong Zhang , Yunsong Yu , Xiaoting Hua

引用次数: 0

Targeting SLC7A11 with sorafenib sensitizes stereotactic body radiotherapy in colorectal cancer liver metastasis 索拉非尼靶向SLC7A11的立体定向放疗对结直肠癌肝转移的增敏作用

IF 15.8 1区医学 Q1 PHARMACOLOGY & PHARMACY

Drug Resistance Updates

Pub Date : 2025-07-01 Epub Date: 2025-05-10 DOI: 10.1016/j.drup.2025.101250

Jiashuai He , Yiran Zhang , Simin Luo , Zhan Zhao , Tianmu Mo , Hanyang Guan , Haoquan Li , Zili Bian , Xiangwei Zhang , Shenghui Qiu , Shijin Liu , Wang Tang , Bo Shi , Minfeng Chen , Dongmei Zhang , Yunlong Pan , Jinghua Pan

Colorectal cancer (CRC) with hepatic metastasis is associated with poor prognosis. Stereotactic body radiotherapy (SBRT) can provide local control for unresectable hepatic metastases of patients with CRC. However, the mechanisms of responsiveness to SBRT in metastatic CRC (mCRC) remain unclear. We aimed to identify a strategy to enhance the efficacy of SBRT in patients with CRC liver metastases and its mechanisms. Transcriptomic sequencing of CRC cells exposed to SBRT revealed that SBRT inhibited SLC7A11 expression. Downregulation of SLC7A11 enhanced the sensitivity of CRC cells to SBRT via ferroptosis. SBRT diminished the ability of tumor cells to sustain oxidative stress by impeding the phosphorylation of JNK and c-Jun and the transcription of NRF2. Furthermore, sorafenib, which targets SLC7A11, exerted inhibitory effects on tumor growth when used in combination with SBRT. A phase II clinical trial confirmed that sorafenib combined with SBRT overcame the resistance of liver mCRC with high SLC7A11 expression by inducing ferroptosis. The combination of SBRT and sorafenib demonstrated favorable clinical effects and safety, making it a good option for patients with CRC liver metastasis.

Statement of Significance

A novel strategy using the combination of SBRT and sorafenib for the treatment of patients with CRC hepatic metastasis was investigated. This strategy overcomes the radiation therapy resistance of mCRC by inhibiting SLC7A11 expression and promoting ferroptosis.

结直肠癌伴肝转移的预后较差。立体定向放射治疗（SBRT）可以为结直肠癌患者不可切除的肝转移提供局部控制。然而，转移性CRC （mCRC）对SBRT的反应机制尚不清楚。我们的目的是确定一种策略来提高SBRT在结直肠癌肝转移患者中的疗效及其机制。暴露于SBRT的CRC细胞的转录组测序显示，SBRT抑制SLC7A11的表达。SLC7A11的下调通过铁凋亡增强了CRC细胞对SBRT的敏感性。SBRT通过抑制JNK和c-Jun的磷酸化以及NRF2的转录，降低了肿瘤细胞维持氧化应激的能力。此外，靶向SLC7A11的索拉非尼与SBRT联合使用时，对肿瘤生长具有抑制作用。一项II期临床试验证实，索拉非尼联合SBRT通过诱导铁上吊克服了SLC7A11高表达的肝mCRC的耐药性。SBRT联合索拉非尼的临床疗效和安全性良好，是结直肠癌肝转移患者的良好选择。

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引用次数: 0