Drug Resistance Updates最新文献

{"title":"UBL3 governs VEGFR inhibitor resistance by activating NOTCH signaling in renal cell carcinoma","authors":"Diaoyi Tan ,&nbsp;Yuzhong Ye ,&nbsp;Daojia Miao ,&nbsp;Chuanyi Zhao ,&nbsp;Songming Wu ,&nbsp;Jian Shi ,&nbsp;Junkai Yang ,&nbsp;Kanglin Fang ,&nbsp;Feiyi Lu ,&nbsp;Qingyang Lv ,&nbsp;Jinshuo Gong ,&nbsp;Hongmei Yang ,&nbsp;Wen Xiao ,&nbsp;Zhiyong Xiong ,&nbsp;Xiaoping Zhang ,&nbsp;Hailong Ruan","doi":"10.1016/j.drup.2025.101332","DOIUrl":"10.1016/j.drup.2025.101332","url":null,"abstract":"<div><h3>Background</h3><div>Targeted therapy is the first-line treatment for patients with metastatic renal cell carcinoma (RCC), with vascular endothelial growth factor receptor inhibitors (VEGFRis) constituting the bulk of regimens used. Although the repertoire of VEGFRis for RCC now spans from sunitinib to cabozantinib, resistance to treatments has emerged as a common and prominent challenge. Thus, identifying novel therapeutic targets has become essential for enhancing the antitumor efficacy of current treatments and inhibiting RCC progression.</div></div><div><h3>Method</h3><div>To investigate the potential mechanisms underlying VEGFRi resistance in RCC, we performed a genome-wide CRISPR/Cas9 library screen under sunitinib and cabozantinib treatment and identified UBL3 as a key driver of VEGFRi resistance in RCC cells. The critical role of UBL3 in promoting VEGFRi resistance was validated using CCK8 assays, flow cytometry, TUNEL assays, and bioinformatics analyses. To elucidate the molecular mechanisms underlying UBL3, we utilized western blotting, RNA sequencing, chromatin immunoprecipitation, small extracellular vesicles (sEVs) isolation, and Astral-DIA proteomics. The contribution of UBL3 to VEGFRi resistance was further confirmed through comprehensive in vitro and in vivo experiments.</div></div><div><h3>Results</h3><div>UBL3 was confirmed to suppress apoptosis and promote VEGFRi resistance through NOTCH signaling activation. Further investigations highlighted the importance of NOTCH signaling in VEGFRi resistance in RCC via the NOTCH-PTEN-AKT and NOTCH-FOS pathways and revealed the mechanisms by which UBL3 activated NOTCH signaling. On the one hand, UBL3 formed complex with NOTCH2 and ADAM17 simultaneously, accelerating ADAM17-mediated cleavage of NOTCH2. On the other hand, UBL3-modified NOTCH2 was sorted into sEVs, which were taken up by recipient cells, activating NOTCH signaling and thereby transmitting VEGFRi resistance. Finally, lipid nanoparticle-mediated delivery of the CRISPR/Cas9 knockout system targeting UBL3 effectively restored the sensitivity of RCC tumors to VEGFRis.</div></div><div><h3>Conclusion</h3><div>This study emphasized the importance of UBL3 in VEGFRi resistance in RCC and proposed that UBL3 activated NOTCH signaling through two distinct pathways, thereby suppressing cancer apoptosis and promoting resistance to VEGFRis. These findings provided a solid scientific foundation and paved the way for the development of novel therapeutic strategies for patients with advanced RCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101332"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145657171","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":"Novel quinoxaline-based survivin degraders overcome docetaxel-resistance in castration-resistant prostate cancer","authors":"Caoqinglong Huang ,&nbsp;Xunzhen Zheng ,&nbsp;Qingbin Cui ,&nbsp;Robert C. Peery ,&nbsp;Zizheng Dong ,&nbsp;Xiaohong Li ,&nbsp;Jing-Yuan Liu ,&nbsp;Jian-Ting Zhang","doi":"10.1016/j.drup.2026.101356","DOIUrl":"10.1016/j.drup.2026.101356","url":null,"abstract":"<div><div>Survivin, a homodimeric protein in the Inhibitor of Apoptosis Protein (IAP) family, plays a dual role in apoptosis inhibition and cell cycle regulation. Overexpressed in many cancers but absent in most adult tissues, survivin is a compelling therapeutic target linked to disease progression, aggressiveness, and drug resistance. However, its structural properties render it “undruggable” by conventional approaches. Here, we present a transformative strategy to overcome this challenge by targeting survivin’s hydrophobic dimerization interface, inducing proteasome-dependent degradation. Building on the initial discovery of the survivin degrader LQZ-7I, we developed optimized analogs with significantly enhanced potency through medicinal chemistry. Our top-performing compounds, 7I10 and 7I14, selectively disrupt survivin dimerization, leading to its degradation and spontaneous apoptosis in castration-resistant prostate cancer (CRPC) cells. We also showed that survivin contributes to acquired resistance to docetaxel, the frontline chemotherapy for metastatic CRPC, and that the survivin degraders exhibit potent synergy with docetaxel, and the combination of 7I14 and docetaxel synergistically eliminates CRPC xenografts without added toxicity. This work introduces a first-in-class therapeutic approach that overcomes long-standing barriers to drugging survivin, offering a new avenue for combating docetaxel-resistant metastatic CRPC. With robust efficacy, a favorable safety profile, and potential for clinical translation, 7I10 and 7I14 represent significant advancements in the development of targeted cancer therapies to overcome docetaxel resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101356"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956675","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":"Inhibitors of cellular RSK isoforms exhibit anti-SARS-CoV-2 activity, enhance efficacy of direct-acting antivirals, and suppress emergence of resistance","authors":"André Schreiber ,&nbsp;Benjamin Ambrosy ,&nbsp;Darisuren Anhlan ,&nbsp;Stefan Bletz ,&nbsp;Alexander Mellmann ,&nbsp;Stephan Ludwig","doi":"10.1016/j.drup.2026.101357","DOIUrl":"10.1016/j.drup.2026.101357","url":null,"abstract":"<div><div>Identifying novel antiviral treatment strategies to expand the existing repertoire of available small-molecule drugs is an important task in addressing both current and emerging viral diseases. Host-targeting antivirals (HTA) and direct-acting antivirals (DAA) represent two classes of such small-molecule drugs. While both classes of drugs are active in a stand-alone treatment, it may be a promising approach to increase the benefits of both by using them in combination which may lead to a synergistic amplification of the antiviral effects. In this study, we show that SARS-CoV-2 is sensitive to the inhibition of the cellular 90 kDa ribosomal S6 kinase (RSK) family, which are direct downstream effectors of the Raf/MEK/ERK signaling pathway. Specific RSK inhibitors (BI-D1870, BRD 7389) showed anti-SARS-CoV-2 properties in single and combination treatment. We could evaluate synergistic properties with the DAAs Remdesivir (RDV) and Nirmatrelvir (NTV). Serial passaging of δ-B.1.617.2 variant under permanent drug pressure did not alter the susceptibility to the RSK inhibitors, while attenuated responsiveness was found for the DAAs. Interestingly, this diminished drug sensitivity did not occur when BRD 7389 and NTV were combined. Furthermore, we demonstrated that combining RSK inhibitors with DAAs not only helps prevent the development of reduced drug susceptibility but may also synergistically compensate for diminished DAA sensitivity, a phenotype that was not found for combined DAA (NTV + RDV) treatments. These results are indicative of the potency and benefit of a combination treatment with DAAs and HTAs, which may likely be the basis for safe and long-lasting novel antiviral therapeutic approaches.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101357"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032879","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 profiling of chemotherapy-resistant breast cancer reveals DNA methylation remodeling associated with the acquisition of paclitaxel resistance","authors":"Lenka Trnkova ,&nbsp;Monika Burikova ,&nbsp;Andrea Soltysova ,&nbsp;Andrej Ficek ,&nbsp;Jana Plava ,&nbsp;Andrea Cumova ,&nbsp;Lucia Rojikova ,&nbsp;Kristina Jakic ,&nbsp;Eva Sedlackova ,&nbsp;Boris Tichy ,&nbsp;Vojtech Bystry ,&nbsp;Florence Busato ,&nbsp;Yimin Shen ,&nbsp;Miroslava Matuskova ,&nbsp;Lucia Kucerova ,&nbsp;Geir Frode Øy ,&nbsp;Gunhild Mari Mælandsmo ,&nbsp;Thomas Fleischer ,&nbsp;Jorg Tost ,&nbsp;Svetlana Miklikova ,&nbsp;Bozena Smolkova","doi":"10.1016/j.drup.2026.101350","DOIUrl":"10.1016/j.drup.2026.101350","url":null,"abstract":"<div><h3>Aims</h3><div>Chemotherapy resistance remains a major challenge in breast cancer (BC) treatment. This study aimed to investigate the role of DNA methylation in this complex process and evaluate the potential of the DNA methyltransferase inhibitor decitabine (DAC) in restoring chemosensitivity.</div></div><div><h3>Methods</h3><div>Paclitaxel (PAC)- and doxorubicin (DOX)- resistant BC cell lines were derived from luminal A (T-47D), triple-negative (MDA-MB-231), and HER2-positive (JIMT-1) models and characterized by molecular profiling and functional assays. The therapeutic effects of DAC and DOX were assessed in MDA-MB-231 xenografts, and integrative analyses of DNA methylation and gene expression identified pathways associated with resistance. Follow-up analyses were performed in PAC-resistant MAS98.12 patient-derived xenografts (PDX) and in clinical samples from the NeoAva trial (NCT00773695).</div></div><div><h3>Results</h3><div>Resistant cells exhibited a slow-cycling phenotype, reduced tumorigenicity, and widespread genomic alterations. PAC-resistant xenografts showed extensive methylation and transcriptomic reprogramming, partly restored by DAC, which increased Ki-67 expression and enhanced DOX responsiveness. In contrast, PDX tumors displayed less pronounced changes, predominantly hypomethylation, indicating distinct resistance mechanisms. Importantly, xenograft-derived CpG signatures stratified NeoAva patients by treatment response.</div></div><div><h3>Conclusions</h3><div>Chemoresistance in BC involves extensive genomic and epigenetic remodeling. Although DAC can modulate methylation and tumor phenotype, rational drug combinations will be required to overcome resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101350"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145895426","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":"Acetylation-mediated fluconazole inactivation: A novel antifungal resistance mechanism","authors":"Ludmila Gouveia-Eufrasio ,&nbsp;Gustavo José Cota de Freitas ,&nbsp;Danielle Letícia da Silva ,&nbsp;Iara Rinco Silva ,&nbsp;Daniel Santana de Carvalho ,&nbsp;Milton T. Drott ,&nbsp;Bruna Carolina Teixeira Almeida ,&nbsp;Cesar da Silva Santana Moura ,&nbsp;Beatriz Murta Rezende Moraes Ribeiro ,&nbsp;Maria Fernanda Liphaus Almeida Negreli ,&nbsp;Lucas Cecilio Vilar ,&nbsp;Silvia Maria Cordeiro Werneck ,&nbsp;Grace Santos Tavares Avelar ,&nbsp;Álan Natanael Pereira Gomes ,&nbsp;Isabela Lima de Miranda ,&nbsp;Mariana Guerra de Aguilar ,&nbsp;Rossimiriam Pereira de Freitas ,&nbsp;Luana Rossato ,&nbsp;Rafael Wesley Bastos ,&nbsp;Lívia Kmetzsch ,&nbsp;Daniel Assis Santos","doi":"10.1016/j.drup.2026.101359","DOIUrl":"10.1016/j.drup.2026.101359","url":null,"abstract":"<div><div>Antifungal resistance is considered a global health threat. However, enzymatic inactivation of antifungals, a common mechanism seen in antibacterial resistance, has not yet been described in fungi. From a One Health perspective, this study demonstrates that <em>Cryptococcus deuterogattii</em> and <em>C. neoformans</em>, the leading agents of cryptococcosis, enzymatically inactivate fluconazole. Agrochemicals induce the overexpression of genes that code for acetyltransferases, specifically GCN5 and NAT10. These enzymes catalyze the acetylation of fluconazole into <em>O</em>-acetyl-fluconazole. This metabolite is unable to properly bind to 14-α-demethylase, the azole target, abolishing the antifungal activity. GCN5 and NAT10 inhibitors constrained acetylation and restored fluconazole activity, highlighting their potential as therapeutic adjuvants. The same phenotype was observed in other fungal species, suggesting broader relevance. Furthermore, <em>O</em>-acetyl-fluconazole was also detected in cerebrospinal fluid from cryptococcal meningitis patients undergoing fluconazole treatment. These findings reveal a previously unrecognized antifungal resistance mechanism and suggest that environmental traits shape clinically relevant resistance through conserved enzymatic pathways.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101359"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146022982","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":"Overcoming resistance in oncolytic virotherapy: Nano-engineered solutions for systemic delivery and efficacy boost","authors":"Xiaoxiao Wang ,&nbsp;Rangrang Fan ,&nbsp;Geyuan Wang ,&nbsp;Bo Han ,&nbsp;Liangxue Zhou ,&nbsp;Aiping Tong ,&nbsp;Bingwen Zou ,&nbsp;Gang Guo","doi":"10.1016/j.drup.2025.101345","DOIUrl":"10.1016/j.drup.2025.101345","url":null,"abstract":"<div><div>Oncolytic virotherapy (OVT) has emerged as a transformative cancer treatment, leveraging tumor-selective viral replication to induce direct oncolysis and stimulate systemic antitumor immunity. Despite clinical advancements, including the FDA-approved T-VEC and subsequent agents, significant challenges remain, particularly in systemic delivery and therapeutic efficacy optimization. Intratumoral administration is largely restricted to superficial lesions, whereas intravenous delivery is hindered by rapid immune clearance due to viral antigen exposure. Additionally, insufficient antitumor efficacy presents another major hurdle, driving the growing trend of combinatorial therapies that exert synergistic effects. To overcome these barriers, nanotechnology-driven strategies, encompassing masking, targeting, and arming approaches, are revolutionizing OVT by enhancing viral stealth, improving tumor specificity, and amplifying therapeutic efficacy. Furthermore, considering biosafety concerns associated with live viral therapeutics, alternative functional nanoparticles that mimic oncolytic virus activity have been developed. These include synthetic oncolytic viruses, oncolytic peptides and polymers empowered by nanotechnology, and structurally mimetic nanoparticles. These engineered nanosystems have demonstrated potent oncolytic activity, positioning them as promising alternatives to traditional OVs while retaining their tumor-lytic functions. In this review, we explore how nanotechnology is redefining oncolytic virotherapy, focusing on masking, targeting, and arming nano-strategies. Additionally, we comprehensively examine the potential of nanoparticles to mimic and even replace oncolytic viruses, offering new avenues for enhanced cancer treatment.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101345"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822700","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":"Hyperbaric oxygen targets RCN1 to modulate ER-mitochondria crosstalk and ameliorate sorafenib resistance in hepatocellular carcinoma","authors":"Yuxi Lin ,&nbsp;Feng Zhang ,&nbsp;Weimin Guo ,&nbsp;Jiaxin Guo ,&nbsp;Xu Qiu ,&nbsp;Yuelin Sun ,&nbsp;Rong Li ,&nbsp;Zihao Pan ,&nbsp;Wentao Zhong ,&nbsp;Min Yu ,&nbsp;Jun Zheng ,&nbsp;Jingwen Peng ,&nbsp;Weifeng Hong","doi":"10.1016/j.drup.2025.101342","DOIUrl":"10.1016/j.drup.2025.101342","url":null,"abstract":"<div><div>The emergence of resistance to tyrosine kinase inhibitors (TKIs) compromises their clinical benefits in patients with hepatocellular carcinoma (HCC), in part due to adaptive responses triggered by tumor hypoxia. In this study, we leverage hyperbaric oxygen (HBO) therapy as a sensitizing strategy in sorafenib-resistant HCC. We demonstrate that HBO significantly enhances the anti-tumor effect of sorafenib by stimulating calcium transfer from the endoplasmic reticulum (ER) to mitochondria, resulting in ER stress and mitochondrial dysfunction. Mechanistically, we show that hypoxia upregulates HNF4A, a transcriptional suppressor of RCN1, and HBO therapy effectively inhibits this hypoxia-driven HNF4A/RCN1 axis. Downregulation of RCN1, a calcium-binding protein overexpressed in sorafenib-resistant HCC, strengthens ER-mitochondria coupling. Subsequently, RCN1 suppression attenuates its interaction with IP3R1 through the EFh1/2 domain, facilitating IP3R1-GRP75 dissociation and the activation of mitochondrial calcium-uptake machinery. Using its EF-hand domains, RCN1 senses fluctuations in ER calcium concentration and accordingly employs a feedback mechanism to fine-tune its binding to IP3R1. In xenograft and spontaneous models, combined HBO-TKIs treatment delays tumor progression and modulates the HNF4A/RCN1 axis. Taken together, our findings elucidate a hitherto uncharacterized role of HBO in regulating ER-mitochondria calcium homeostasis and support its clinical application as an adjunctive therapy in TKI-resistant HCC.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101342"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145731944","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":"AMPKα2 attenuates doxorubicin induced ferroptosis by promoting NCOA4 degradation in triple negative breast cancer","authors":"Xinjun Liu ,&nbsp;Zizhen Si ,&nbsp;Linbo Li ,&nbsp;Miao Zhou ,&nbsp;Ki-Young Lee ,&nbsp;Xidi Wang","doi":"10.1016/j.drup.2025.101349","DOIUrl":"10.1016/j.drup.2025.101349","url":null,"abstract":"<div><h3>Aims</h3><div>Triple negative breast cancer (TNBC) is an aggressive type of breast cancer with limited therapeutic options and frequent chemoresistance. AMPK catalytic α-subunit 2 (AMPKα2) is implicated in development of chemoresistance in various cancers. However, the role of AMPKα2 in doxorubicin (DOX)-resistance in TNBC remains to be investigated.</div></div><div><h3>Methods</h3><div>The levels of AMPKα2 in DOX-resistant TNBC was examined by Western blotting. AMPKα2 functions on DOX induced ferroptosis were assessed by lipid peroxidation, intracellular iron, MDA, and GSH detection assays. Western blotting, qRT-PCR, co-IP, immunofluorescence staining and KFERQ-mCherry reporter assay were performed to demonstrate the role of AMPKα2 and its association with NCOA4 degradation.</div></div><div><h3>Results</h3><div>AMPKα2, rather than AMPKα1, was upregulated in DOX-resistant TNBC cells. AMPKα2 inhibited DOX-induced ferroptosis by suppressing NCOA4. AMPKα2 phosphorylated NCOA4 at S151, which enhanced the recognition of NCOA4 by HSC70, and the formation of NCOA4/HSC70/LAMP-2A complex to initiate CMA pathway mediated NCOA4 degradation. S151A mutation or AMPKα inhibitor abolished these biological effects and increased the vulnerability to DOX-induced ferroptosis.</div></div><div><h3>Conclusions</h3><div>AMPKα2 suppressed DOX-induced ferroptosis through phosphorylating NCOA4 at S151 to induce its CMA pathway dependent degradation. Targeting AMPKα2 could be a potential strategy to overcome DOX resistance in TNBC patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101349"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145894006","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":"The hallmarks of oncogenic signaling: From pathways to resistance in cancer therapy","authors":"Muhammad Tufail ,&nbsp;Kunxiang Gong ,&nbsp;Bushra Ijaz ,&nbsp;Harsh Patel ,&nbsp;Weng-Onn Lui ,&nbsp;Xiumei Wang ,&nbsp;Jie Li","doi":"10.1016/j.drup.2026.101355","DOIUrl":"10.1016/j.drup.2026.101355","url":null,"abstract":"<div><div>Oncogenic signal transduction pathways play pivotal roles in tumor progression by regulating essential cellular processes such as proliferation, survival, angiogenesis, invasion, and immune evasion. These pathways are frequently deregulated in cancer due to genetic mutations, epigenetic modifications, or microenvironmental influences. These genetic or epigenetics shifts enable cancer cells to bypass growth suppressors, resist apoptosis, and sustain uncontrolled growth. While targeted therapies have shown promise in inhibiting these signaling cascades, therapeutic resistance and tumor heterogeneity remain major obstacles. To address these limitations, emerging strategies, including combination therapies, next-generation kinase inhibitors, and immunomodulatory approaches, are being developed to overcome these challenges. This review explores the molecular mechanisms underlying oncogenic pathway activation, their contributions to hallmark cancer traits and resistance, and therapeutic advancements targeting these pathways. By understanding these signaling networks, we aim to highlight opportunities for improving cancer treatment and addressing therapeutic resistance in the evolving landscape of oncology.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101355"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145956676","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":"IFNα2b modulates anti-tumor immune responses involving STAT3-associated dendritic cell dysfunction in JAK2v617f-positive myeloproliferative neoplasms","authors":"Lijun Fang ,&nbsp;Rongfeng Fu ,&nbsp;Huan Dong ,&nbsp;Wenhui Zhang ,&nbsp;Yuchen Gao ,&nbsp;Yanmei Xu ,&nbsp;Wenjing Gu ,&nbsp;Zixuan Liu ,&nbsp;Huiyuan Li ,&nbsp;Wentian Wang ,&nbsp;Xiaolei Pei ,&nbsp;Ying Chi ,&nbsp;Yuan Zhou ,&nbsp;Jun Wei ,&nbsp;Ying Wang ,&nbsp;Lei Zhang","doi":"10.1016/j.drup.2026.101352","DOIUrl":"10.1016/j.drup.2026.101352","url":null,"abstract":"<div><h3>Aims</h3><div>To define <em>JAK2v617f</em>-induced immune alterations, focusing on STAT3-mediated dendritic cell dysfunction, and evaluate whether IFNα2b restores anti-tumor immunity in <em>JAK2v617f</em>-positive myeloproliferative neoplasms.</div></div><div><h3>Methods</h3><div>Integrated flow cytometry and single-cell RNA sequencing profiled immune landscapes and signaling pathways, while functional assays assessed dendritic cell differentiation, T cell activation, and IFNα2b-mediated immune restoration.</div></div><div><h3>Results</h3><div><em>JAK2v617f</em> was associated with increased STAT3 activation in myeloid cells, accompanied by elevated expression of immunosuppressive mediators such as FGL2, impaired monocyte-to-DC differentiation, reduced cDC1/cDC2 subsets, and diminished T cell activation, consistent with an immunosuppressive immune landscape. IFNα2b treatment was associated with attenuation of STAT3/FGL2 signaling and partial restoration of DC-mediated T cell priming, with more pronounced immunomodulatory effects observed in <em>JAK2v617f</em>-positive myeloproliferative neoplasms compared with other subtypes.</div></div><div><h3>Conclusions</h3><div>Our findings indicate that <em>JAK2v617f</em> is associated with STAT3-dependent dendritic cell dysfunction that contributes to an immunosuppressive milieu. IFNα2b modulates this pathway and partially restores DC–T cell interactions, highlighting its potential as an immunomodulatory strategy in <em>JAK2v617f</em>-positive myeloproliferative neoplasms.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101352"},"PeriodicalIF":21.7,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145902552","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}