Pub Date : 2026-01-28DOI: 10.1016/j.drup.2026.101361
Wenjia Zhang , Junjie Ma , Yuka Yanagi , Ping Yin , Jin Cheng , Yi Wang , Nan Hong , Jens Ricke , Huadan Xue , Sihang Cheng
Cancer remains a leading cause of global mortality, with therapeutic resistance posing a formidable clinical obstacle. Inorganic nanotheranostics-multifunctional platforms integrating diagnostic and therapeutic capabilities-offer a promising strategy to overcome this barrier. This review systematically examines how distinct classes of inorganic nanomaterials (including iron, gadolinium, titanium, gold, manganese, carbon, and silicon-based systems) are engineered to counteract specific resistance mechanisms through unique physicochemical properties and biological interactions. We highlight their roles in enhancing drug delivery, modulating the tumor microenvironment, enabling precise imaging, and synergizing with various treatment modalities such as chemotherapy, radiotherapy, and immunotherapy. Advances in stimulus-responsive design, targeted delivery, and combinatorial therapies are discussed. Finally, we critically evaluate the translational challenges-including pharmacokinetics, long-term safety, and manufacturing scalability-and outline future directions toward clinically effective, personalized nanotheranostic interventions in oncology.
{"title":"Overcoming therapeutic resistance in oncology: The prospects of inorganic nanotheranostics","authors":"Wenjia Zhang , Junjie Ma , Yuka Yanagi , Ping Yin , Jin Cheng , Yi Wang , Nan Hong , Jens Ricke , Huadan Xue , Sihang Cheng","doi":"10.1016/j.drup.2026.101361","DOIUrl":"10.1016/j.drup.2026.101361","url":null,"abstract":"<div><div>Cancer remains a leading cause of global mortality, with therapeutic resistance posing a formidable clinical obstacle. Inorganic nanotheranostics-multifunctional platforms integrating diagnostic and therapeutic capabilities-offer a promising strategy to overcome this barrier. This review systematically examines how distinct classes of inorganic nanomaterials (including iron, gadolinium, titanium, gold, manganese, carbon, and silicon-based systems) are engineered to counteract specific resistance mechanisms through unique physicochemical properties and biological interactions. We highlight their roles in enhancing drug delivery, modulating the tumor microenvironment, enabling precise imaging, and synergizing with various treatment modalities such as chemotherapy, radiotherapy, and immunotherapy. Advances in stimulus-responsive design, targeted delivery, and combinatorial therapies are discussed. Finally, we critically evaluate the translational challenges-including pharmacokinetics, long-term safety, and manufacturing scalability-and outline future directions toward clinically effective, personalized nanotheranostic interventions in oncology.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"86 ","pages":"Article 101361"},"PeriodicalIF":21.7,"publicationDate":"2026-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146071803","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}
Pub Date : 2026-01-23DOI: 10.1016/j.drup.2026.101360
Minghui Zhang , Lijun Li , Haihong Pu , Yan Wang , Xiaoxin Zhang , Xiaotian Guo , Yanbin Zhao , Qingwei Meng , Mingzhu Yin
Tumor organoids represent a transformative tool in cancer research, as they retain the genetic and phenotypic features of parental tumors and accurately recapitulate their heterogeneity. However, one of the limitations of tumor organoids lies in the lack of immune and stromal cells in the tumor microenvironment (TME). To address this challenge, tumor immune organoids have been developed, which contain complex immune and stromal compartments beyond preserving tumor architecture. Tumor immune organoids show great potential for studying personalized immunotherapy responses and mechanisms of immunotherapy resistance. However, integrating the models into clinical practice remains challenging. In this Review, we outline currently available and rapidly evolving tumor immune organoids that recapitulate the TME and immunotherapy effects. These tumor immune organoids can be established by co-culturing traditional tumor organoids with stromal and immune cells, as well as preserving the TME using microfluidic and air-liquid interface (ALI) culture technologies. Additionally, we delineate the applications of tumor immune organoids for unravelling tumor-intrinsic and -extrinsic immunotherapy resistance mechanisms, predicting immunotherapy efficacy, and facilitating novel drug screening. Finally, we highlight the current challenges of organoid culture technology that need to be addressed for its broader applications, both in basic and translational cancer research. This review provides a theoretical foundation for future research on the application of tumor immune organoids to investigate immunotherapy resistance mechanisms and develop personalized immunotherapies. With continuous advancements, tumor immune organoids are expected to play an increasingly indispensable role in cancer immunotherapy, providing patients with more effective and tailored treatment options.
{"title":"Tumor immune organoids in immunotherapy resistance and drug screening","authors":"Minghui Zhang , Lijun Li , Haihong Pu , Yan Wang , Xiaoxin Zhang , Xiaotian Guo , Yanbin Zhao , Qingwei Meng , Mingzhu Yin","doi":"10.1016/j.drup.2026.101360","DOIUrl":"10.1016/j.drup.2026.101360","url":null,"abstract":"<div><div>Tumor organoids represent a transformative tool in cancer research, as they retain the genetic and phenotypic features of parental tumors and accurately recapitulate their heterogeneity. However, one of the limitations of tumor organoids lies in the lack of immune and stromal cells in the tumor microenvironment (TME). To address this challenge, tumor immune organoids have been developed, which contain complex immune and stromal compartments beyond preserving tumor architecture. Tumor immune organoids show great potential for studying personalized immunotherapy responses and mechanisms of immunotherapy resistance. However, integrating the models into clinical practice remains challenging. In this Review, we outline currently available and rapidly evolving tumor immune organoids that recapitulate the TME and immunotherapy effects. These tumor immune organoids can be established by co-culturing traditional tumor organoids with stromal and immune cells, as well as preserving the TME using microfluidic and air-liquid interface (ALI) culture technologies. Additionally, we delineate the applications of tumor immune organoids for unravelling tumor-intrinsic and -extrinsic immunotherapy resistance mechanisms, predicting immunotherapy efficacy, and facilitating novel drug screening. Finally, we highlight the current challenges of organoid culture technology that need to be addressed for its broader applications, both in basic and translational cancer research. This review provides a theoretical foundation for future research on the application of tumor immune organoids to investigate immunotherapy resistance mechanisms and develop personalized immunotherapies. With continuous advancements, tumor immune organoids are expected to play an increasingly indispensable role in cancer immunotherapy, providing patients with more effective and tailored treatment options.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101360"},"PeriodicalIF":21.7,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146032878","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}
Pub Date : 2026-01-23DOI: 10.1016/j.drup.2026.101359
Ludmila Gouveia-Eufrasio , Gustavo José Cota de Freitas , Danielle Letícia da Silva , Iara Rinco Silva , Daniel Santana de Carvalho , Milton T. Drott , Bruna Carolina Teixeira Almeida , Cesar da Silva Santana Moura , Beatriz Murta Rezende Moraes Ribeiro , Maria Fernanda Liphaus Almeida Negreli , Lucas Cecilio Vilar , Silvia Maria Cordeiro Werneck , Grace Santos Tavares Avelar , Álan Natanael Pereira Gomes , Isabela Lima de Miranda , Mariana Guerra de Aguilar , Rossimiriam Pereira de Freitas , Luana Rossato , Rafael Wesley Bastos , Lívia Kmetzsch , Daniel Assis Santos
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 Cryptococcus deuterogattii and C. neoformans, 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 O-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, O-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.
{"title":"Acetylation-mediated fluconazole inactivation: A novel antifungal resistance mechanism","authors":"Ludmila Gouveia-Eufrasio , Gustavo José Cota de Freitas , Danielle Letícia da Silva , Iara Rinco Silva , Daniel Santana de Carvalho , Milton T. Drott , Bruna Carolina Teixeira Almeida , Cesar da Silva Santana Moura , Beatriz Murta Rezende Moraes Ribeiro , Maria Fernanda Liphaus Almeida Negreli , Lucas Cecilio Vilar , Silvia Maria Cordeiro Werneck , Grace Santos Tavares Avelar , Álan Natanael Pereira Gomes , Isabela Lima de Miranda , Mariana Guerra de Aguilar , Rossimiriam Pereira de Freitas , Luana Rossato , Rafael Wesley Bastos , Lívia Kmetzsch , 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":"2026-01-23","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}
Pub Date : 2026-01-21DOI: 10.1016/j.drup.2026.101357
André Schreiber , Benjamin Ambrosy , Darisuren Anhlan , Stefan Bletz , Alexander Mellmann , Stephan Ludwig
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.
{"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 , Benjamin Ambrosy , Darisuren Anhlan , Stefan Bletz , Alexander Mellmann , 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":"2026-01-21","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}
Pub Date : 2026-01-19DOI: 10.1016/j.drup.2026.101358
Shuyao Zhu , Feiyu Yu , Bingqing Yang , Miao Zhang , Haijie Zhang , Zhiqiang Wang , Yuan Liu
Plasmid-mediated conjugative transfer drives the global dissemination of antimicrobial resistance, posing a global threat to public health. Besides extruding antibiotics, bacterial multidrug efflux pumps modulate virulence, yet their influence on resistance plasmid spread in antibiotic-free settings remains undefined. Herein, we demonstrate that the AcrAB-TolC efflux pump is critical for the horizontal transfer of model plasmid RP4–7 and diverse clinical resistance plasmids. Single deletions of acrA, acrB or tolC significantly reduce plasmid transfer, and complementation fully restores conjugative frequencies to control levels. Mechanistic investigations reveal that acrB deficiency reduces interbacterial contact, diminishes energy metabolism, and impairs activity of the glutamate decarboxylase, quorum sensing and the conjugative systems. Furthermore, we identify chlorpromazine as a potential AcrB ligand, which blocks plasmid transfer both in vivo and in vitro. Collectively, our findings reveal the role of efflux pumps in plasmid transfer and underscore AcrB as a druggable target to curtail the spread of antibiotic resistance.
{"title":"Deciphering the roles of AcrAB-TolC efflux pump in promoting the transmission of antibiotic resistance","authors":"Shuyao Zhu , Feiyu Yu , Bingqing Yang , Miao Zhang , Haijie Zhang , Zhiqiang Wang , Yuan Liu","doi":"10.1016/j.drup.2026.101358","DOIUrl":"10.1016/j.drup.2026.101358","url":null,"abstract":"<div><div>Plasmid-mediated conjugative transfer drives the global dissemination of antimicrobial resistance, posing a global threat to public health. Besides extruding antibiotics, bacterial multidrug efflux pumps modulate virulence, yet their influence on resistance plasmid spread in antibiotic-free settings remains undefined. Herein, we demonstrate that the AcrAB-TolC efflux pump is critical for the horizontal transfer of model plasmid RP4–7 and diverse clinical resistance plasmids. Single deletions of <em>acrA</em>, <em>acrB</em> or <em>tolC</em> significantly reduce plasmid transfer, and complementation fully restores conjugative frequencies to control levels. Mechanistic investigations reveal that <em>acrB</em> deficiency reduces interbacterial contact, diminishes energy metabolism, and impairs activity of the glutamate decarboxylase, quorum sensing and the conjugative systems. Furthermore, we identify chlorpromazine as a potential AcrB ligand, which blocks plasmid transfer both <em>in vivo</em> and <em>in vitro</em>. Collectively, our findings reveal the role of efflux pumps in plasmid transfer and underscore AcrB as a druggable target to curtail the spread of antibiotic resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101358"},"PeriodicalIF":21.7,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146000949","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}
Pub Date : 2026-01-12DOI: 10.1016/j.drup.2026.101356
Caoqinglong Huang , Xunzhen Zheng , Qingbin Cui , Robert C. Peery , Zizheng Dong , Xiaohong Li , Jing-Yuan Liu , Jian-Ting Zhang
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.
Survivin是凋亡抑制蛋白（inhibitor of apoptosis protein， IAP）家族中的一种二聚体蛋白，具有抑制细胞凋亡和调节细胞周期的双重作用。survivin在许多癌症中过表达，但在大多数成人组织中不表达，是与疾病进展、侵袭性和耐药性相关的令人信服的治疗靶点。然而，它的结构特性使其在传统方法中“不可吸毒”。在这里，我们提出了一种变革策略，通过靶向survivin的疏水二聚化界面，诱导蛋白酶体依赖性降解来克服这一挑战。在初步发现的survivin降解剂LQZ-7I的基础上，我们通过药物化学方法开发了具有显著增强效价的优化类似物。我们表现最好的化合物7I10和7I14选择性地破坏survivin二聚化，导致其在去势抵抗性前列腺癌（CRPC）细胞中降解和自发凋亡。我们还表明，survivin有助于对多西他赛（用于转移性CRPC的一线化疗药物）的获得性耐药，survivin降解物与多西他赛表现出强大的协同作用，7I14和多西他赛联合可协同消除CRPC异种移植物，而不会增加毒性。这项工作介绍了一种一流的治疗方法，克服了长期存在的生存素药物障碍，为对抗多西他赛耐药转移性CRPC提供了新的途径。7I10和7I14具有强大的疗效，良好的安全性和临床转化潜力，代表了靶向癌症治疗发展的重大进展，以克服多西他赛耐药。
{"title":"Novel quinoxaline-based survivin degraders overcome docetaxel-resistance in castration-resistant prostate cancer","authors":"Caoqinglong Huang , Xunzhen Zheng , Qingbin Cui , Robert C. Peery , Zizheng Dong , Xiaohong Li , Jing-Yuan Liu , 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":"2026-01-12","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}
Pub Date : 2026-01-12DOI: 10.1016/j.drup.2026.101355
Muhammad Tufail , Kunxiang Gong , Bushra Ijaz , Harsh Patel , Weng-Onn Lui , Xiumei Wang , Jie Li
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.
{"title":"The hallmarks of oncogenic signaling: From pathways to resistance in cancer therapy","authors":"Muhammad Tufail , Kunxiang Gong , Bushra Ijaz , Harsh Patel , Weng-Onn Lui , Xiumei Wang , 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":"2026-01-12","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}
Pub Date : 2026-01-08DOI: 10.1016/j.drup.2026.101354
Marco Pieraccioli , Alessandra Ciucci , Christian Corti , Roberta Mastrantonio , Eleonora Kristina Scarpone , Eleonora Cesari , Alessia Piermattei , Angelo Minucci , Andrea Urbani , Floriana Camarda , Anna Fagotti , Luca Tamagnone , Giovanni Scambia , Camilla Nero , Claudio Sette
Aim
High grade serous ovarian cancer (HGSOC) is the most aggressive subtype of ovarian cancer. HGSOC is characterized by high inter- and intra-tumoral heterogeneity, which contributes to chemotherapy resistance. Patient-derived organoids (PDOs) are valuable preclinical models to elucidate the biology of human cancers and to test their response to treatments. This study aims at characterizing the cellular heterogeneity of PDOs and to uncover vulnerabilities of chemotherapy resistant HGSOC.
Methods
Single-cell transcriptomics of PDOs developed from biopsies of platinum-resistant and platinum-sensitive HGSOC. Chemotherapeutic treatments of HGSOC PDOs and of ascitic-derived ovarian cancer cells and immunohistochemistry analyses of tissues from independent HGSOC patients.
Results
HGSOC PDOs comprise subclusters of cells exhibiting different transcriptional states and patient-specific signatures. Proliferative and non-proliferative subclusters co-exist in PDOs and their relative proportion is altered by chemotherapy. Proliferative cell sub-populations exhibit expression of cell cycle and DNA damage response related genes, whereas non-proliferative sub-populations display inflammatory signatures. Furthermore, sensitivity to platinum-based treatments was inversely correlated with oxidative phosphorylation (OXHPOS) in PDOs, indicating a metabolic switch associated with chemoresistance. Accordingly, platinum-resistant PDOs and ascitic HGSOC cells show higher sensitivity to OXHPOS inhibition. We found that neoadjuvant chemotherapy (NACT) directly up-regulates oncogenic and metabolic pathways that are involved in development of recurrence, such as the MYC and OXPHOS genes. NACT also induces the expression of major histocompatibility complex type II (MHC-II) molecules. Immunohistochemistry confirmed MHC-II up-regulation in post-NACT biopsies, indicating that tumour cells mount a general antigen-presenting response upon chemotherapy, associated with recruitment of infiltrating immune cells.
Conclusion
PDOs maintain the inter- and intra-tumoral cellular heterogeneity of HGSOC. Chemotherapy targets proliferative cell subclusters, sparing non-proliferative ones. Dependency on OXPHOS represents an actionable vulnerability in PDOs, which can be exploited to hijack chemoresistance. Sequential chemotherapy and immunotherapy may also improve clinical response of HGSOC patients.
{"title":"Single-cell transcriptome analysis of patient-derived organoids captures inter- and intratumor heterogeneity and uncovers targetable pathways in high grade serous ovarian cancer","authors":"Marco Pieraccioli , Alessandra Ciucci , Christian Corti , Roberta Mastrantonio , Eleonora Kristina Scarpone , Eleonora Cesari , Alessia Piermattei , Angelo Minucci , Andrea Urbani , Floriana Camarda , Anna Fagotti , Luca Tamagnone , Giovanni Scambia , Camilla Nero , Claudio Sette","doi":"10.1016/j.drup.2026.101354","DOIUrl":"10.1016/j.drup.2026.101354","url":null,"abstract":"<div><h3>Aim</h3><div>High grade serous ovarian cancer (HGSOC) is the most aggressive subtype of ovarian cancer. HGSOC is characterized by high inter- and intra-tumoral heterogeneity, which contributes to chemotherapy resistance. Patient-derived organoids (PDOs) are valuable preclinical models to elucidate the biology of human cancers and to test their response to treatments. This study aims at characterizing the cellular heterogeneity of PDOs and to uncover vulnerabilities of chemotherapy resistant HGSOC.</div></div><div><h3>Methods</h3><div>Single-cell transcriptomics of PDOs developed from biopsies of platinum-resistant and platinum-sensitive HGSOC. Chemotherapeutic treatments of HGSOC PDOs and of ascitic-derived ovarian cancer cells and immunohistochemistry analyses of tissues from independent HGSOC patients.</div></div><div><h3>Results</h3><div>HGSOC PDOs comprise subclusters of cells exhibiting different transcriptional states and patient-specific signatures. Proliferative and non-proliferative subclusters co-exist in PDOs and their relative proportion is altered by chemotherapy. Proliferative cell sub-populations exhibit expression of cell cycle and DNA damage response related genes, whereas non-proliferative sub-populations display inflammatory signatures. Furthermore, sensitivity to platinum-based treatments was inversely correlated with oxidative phosphorylation (OXHPOS) in PDOs, indicating a metabolic switch associated with chemoresistance. Accordingly, platinum-resistant PDOs and ascitic HGSOC cells show higher sensitivity to OXHPOS inhibition. We found that neoadjuvant chemotherapy (NACT) directly up-regulates oncogenic and metabolic pathways that are involved in development of recurrence, such as the <em>MYC</em> and OXPHOS genes. NACT also induces the expression of major histocompatibility complex type II (MHC-II) molecules. Immunohistochemistry confirmed MHC-II up-regulation in post-NACT biopsies, indicating that tumour cells mount a general antigen-presenting response upon chemotherapy, associated with recruitment of infiltrating immune cells.</div></div><div><h3>Conclusion</h3><div>PDOs maintain the inter- and intra-tumoral cellular heterogeneity of HGSOC. Chemotherapy targets proliferative cell subclusters, sparing non-proliferative ones. Dependency on OXPHOS represents an actionable vulnerability in PDOs, which can be exploited to hijack chemoresistance. Sequential chemotherapy and immunotherapy may also improve clinical response of HGSOC patients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101354"},"PeriodicalIF":21.7,"publicationDate":"2026-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925904","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}
Pub Date : 2026-01-06DOI: 10.1016/j.drup.2026.101353
Baris Cerci , Ozge Saatci , Mark Basik , Ozgur Sahin
Antibody-drug conjugate (ADC) is a drug modality where a payload is conjugated to an antibody for its targeted delivery to the cancer cells. In breast cancer, the treatment landscape has changed remarkably in the past decade by the introduction of several effective ADCs in the clinic. However, intrinsic (de novo) or acquired resistance to these treatments is a major obstacle. In this review, we summarize the role of target antigen alterations, cell-intrinsic mechanisms that overcome payload cytotoxicity, and the pro-tumorigenic tumor microenvironment (TME) as the major drivers of resistance to ADCs. Furthermore, we discuss how different mechanisms of ADC resistance are integrated and highlight the most clinically relevant ones. We then provide the current and emerging strategies, such as biomarker-guided drug combinations and novel ADC designs to overcome resistance to ADCs. Finally, we provide future perspectives on the use of preclinical models that better reflect both intratumor heterogeneity and TME, integration of exploratory biomarker analysis through multi-omics of patient biopsies in prospective clinical trials, and development of new ADCs, e.g., bispecific ADCs and identification of novel antigens and/or payloads, to overcome ADC resistance.
{"title":"Mechanisms of resistance to antibody-drug conjugates in breast cancer","authors":"Baris Cerci , Ozge Saatci , Mark Basik , Ozgur Sahin","doi":"10.1016/j.drup.2026.101353","DOIUrl":"10.1016/j.drup.2026.101353","url":null,"abstract":"<div><div>Antibody-drug conjugate (ADC) is a drug modality where a payload is conjugated to an antibody for its targeted delivery to the cancer cells. In breast cancer, the treatment landscape has changed remarkably in the past decade by the introduction of several effective ADCs in the clinic. However, intrinsic (de novo) or acquired resistance to these treatments is a major obstacle. In this review, we summarize the role of target antigen alterations, cell-intrinsic mechanisms that overcome payload cytotoxicity, and the pro-tumorigenic tumor microenvironment (TME) as the major drivers of resistance to ADCs. Furthermore, we discuss how different mechanisms of ADC resistance are integrated and highlight the most clinically relevant ones. We then provide the current and emerging strategies, such as biomarker-guided drug combinations and novel ADC designs to overcome resistance to ADCs. Finally, we provide future perspectives on the use of preclinical models that better reflect both intratumor heterogeneity and TME, integration of exploratory biomarker analysis through multi-omics of patient biopsies in prospective clinical trials, and development of new ADCs, e.g., bispecific ADCs and identification of novel antigens and/or payloads, to overcome ADC resistance.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"85 ","pages":"Article 101353"},"PeriodicalIF":21.7,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145925903","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}
Pub Date : 2026-01-05DOI: 10.1016/j.drup.2026.101352
Lijun Fang , Rongfeng Fu , Huan Dong , Wenhui Zhang , Yuchen Gao , Yanmei Xu , Wenjing Gu , Zixuan Liu , Huiyuan Li , Wentian Wang , Xiaolei Pei , Ying Chi , Yuan Zhou , Jun Wei , Ying Wang , Lei Zhang
Aims
To define JAK2v617f-induced immune alterations, focusing on STAT3-mediated dendritic cell dysfunction, and evaluate whether IFNα2b restores anti-tumor immunity in JAK2v617f-positive myeloproliferative neoplasms.
Methods
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.
Results
JAK2v617f 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 JAK2v617f-positive myeloproliferative neoplasms compared with other subtypes.
Conclusions
Our findings indicate that JAK2v617f 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 JAK2v617f-positive myeloproliferative neoplasms.
{"title":"IFNα2b modulates anti-tumor immune responses involving STAT3-associated dendritic cell dysfunction in JAK2v617f-positive myeloproliferative neoplasms","authors":"Lijun Fang , Rongfeng Fu , Huan Dong , Wenhui Zhang , Yuchen Gao , Yanmei Xu , Wenjing Gu , Zixuan Liu , Huiyuan Li , Wentian Wang , Xiaolei Pei , Ying Chi , Yuan Zhou , Jun Wei , Ying Wang , 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":"2026-01-05","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}
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