Drug Resistance Updates最新文献

{"title":"The uptake of extracellular vesicles: Research progress in cancer drug resistance and beyond","authors":"Luomeng Qian ,&nbsp;Pangzhou Chen ,&nbsp;Shiwu Zhang ,&nbsp;Zhenglu Wang ,&nbsp;Yuan Guo ,&nbsp;Vasili Koutouratsas ,&nbsp;Joshua S. Fleishman ,&nbsp;Chuanqiang Huang ,&nbsp;Sihe Zhang","doi":"10.1016/j.drup.2025.101209","DOIUrl":"10.1016/j.drup.2025.101209","url":null,"abstract":"<div><div>Extracellular vesicles (EVs) are heterogeneous vesicles released by donor cells that can be taken up by recipient cells, thus inducing cellular phenotype changes. Since their discovery decades ago, roles of EVs in modulating initiation, growth, survival and metastasis of cancer have been revealed. Recent studies from multifaceted perspectives have further detailed the contribution of EVs to cancer drug resistance; however, the role of EV uptake in conferring drug resistance seems to be overlooked. In this comprehensive review, we update the EV subtypes and approaches for determining EV uptake. The biological basis of EV uptake is systematically summarized. Moreover, we focus on the diverse uptake mechanisms by which EVs carry out the intracellular delivery of functional molecules and drug resistance signaling. Furthermore, we highlight how EV uptake confers drug resistance and identify potential strategies for targeting EV uptake to overcome drug resistance. Finally, we discuss the research gap on the role of EV uptake in promoting drug resistance. This updated knowledge provides a new avenue to overcome cancer drug resistance by targeting EV uptake.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101209"},"PeriodicalIF":15.8,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077669","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":"Rational design of peptides to overcome drug resistance by metabolic regulation","authors":"Min Sun ,&nbsp;Le He ,&nbsp;Ran Chen ,&nbsp;Mingchen Lv ,&nbsp;Zhe-Sheng Chen ,&nbsp;Zhen Fan ,&nbsp;Yuxiao Zhou ,&nbsp;Jinlong Qin ,&nbsp;Jianzhong Du","doi":"10.1016/j.drup.2025.101208","DOIUrl":"10.1016/j.drup.2025.101208","url":null,"abstract":"<div><div>Chemotherapy is widely used clinically, however, its efficacy is often compromised by the development of drug resistance, which arises from prolonged administration of drugs or other stimuli. One of the driven causes of drug resistance in tumors or bacterial infections is metabolic reprogramming, which alters mitochondrial metabolism, disrupts metabolic pathways and causes ion imbalance. Bioactive peptide materials, due to their biocompatibility, diverse bioactivities, customizable sequences, and ease of modification, have shown promise in overcoming drug resistance. This review provides an in-depth analysis of metabolic reprogramming and associated microenvironmental changes that contribute to drug resistance in common tumors and bacterial infections, suggesting potential therapeutic targets. Additionally, we explore peptide-based materials for regulating metabolism and their potential synergic effect with other therapies, highlighting the mechanisms by which these peptides reverse drug resistance. Finally, we discuss future perspectives and the clinical challenges in peptide-based treatments, aiming to offer insights for overcoming drug-resistant diseases.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101208"},"PeriodicalIF":15.8,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143217854","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":"Structural and functional analyses of STM14_5441-STM14_5442: A potential mechanism for persister formation against aminoglycosides","authors":"Hyun-Jong Eun ,&nbsp;Seok-Won Jang ,&nbsp;Ju-Hyun Park ,&nbsp;Jooyeon Lee ,&nbsp;Ki-Young Lee ,&nbsp;Eun-Jin Lee ,&nbsp;Bong-Jin Lee","doi":"10.1016/j.drup.2025.101210","DOIUrl":"10.1016/j.drup.2025.101210","url":null,"abstract":"<div><h3>Aims</h3><div>The ability to eliminate bacterial persister cells is still a medical challenge that has yet to be overcome. These cells represent a unique subpopulation within bacterial communities and are characterized by a reduced susceptibility to antibiotics with growth retardation. In this study, we investigated the molecular basis of persister formation in <em>Salmonella</em> Typhimurium 14028 s under aminoglycoside stress.</div></div><div><h3>Methods</h3><div>We analyzed the crystal structure of the STM14_5441–STM14_5442 complex, which belongs to the type II toxin-antitoxin system, and identified key ribosome-binding residues in STM14_5441. Changes in the antibiotic susceptibility of <em>Salmonella</em> caused by the loss of the ribosome-binding property of STM14_5441 were assessed. We conducted intracellular ATP assays under aminoglycoside stress and RNA-seq analysis following STM14_5441 induction.</div></div><div><h3>Results</h3><div>Our studies demonstrated the critical role of STM14_5441 in the formation of persister cells in <em>Salmonella</em>, particularly those under aminoglycoside stress. We observed that a loss of ribosome binding in STM14_5441 resulted in increased antibiotic susceptibility. Additionally, intracellular ATP assays revealed increased ATP levels in STM14_5441 induced group, and RNA-seq analysis identified several genes that play a role in this phenomenon.</div></div><div><h3>Conclusions</h3><div>The present data suggest that persister forms under aminoglycoside stress through the following mechanisms: i) inhibition of membrane hyperpolarization by impeding F₁Fo ATP synthase activity and ii) enhanced poststress recovery by ATP storage and increased protein synthesis capacity. Based on this suggestion, we reannotated the STM14_5441-STM14_5442 TA pair as the ResTA (RNA cleavage-induced energy storage toxin-antitoxin) system. Furthermore, new insights into the function of TA systems may lay the groundwork for developing novel strategies to target bacterial persister cells, thereby preventing the accelerated emergence of antibiotic resistance in bacterial populations.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101210"},"PeriodicalIF":15.8,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143142882","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":"B7-H3-liquid biopsy for the characterization and monitoring of the dynamic biology of prostate cancer","authors":"Yong Ju ,&nbsp;Joshua Watson ,&nbsp;Jasmine J. Wang ,&nbsp;Ying-Tzu Yen ,&nbsp;Lilit Gevorkian ,&nbsp;Zijing Chen ,&nbsp;Kai Han Tu ,&nbsp;Brenda Salumbides ,&nbsp;Aaron Phung ,&nbsp;Chen Zhao ,&nbsp;Hyoyong Kim ,&nbsp;You-Ren Ji ,&nbsp;Ryan Y. Zhang ,&nbsp;Junseok Lee ,&nbsp;Jun Gong ,&nbsp;Kevin Scher ,&nbsp;Sungyong You ,&nbsp;Jie-Fu Chen ,&nbsp;Hsian-Rong Tseng ,&nbsp;Yazhen Zhu ,&nbsp;Edwin M. Posadas","doi":"10.1016/j.drup.2025.101207","DOIUrl":"10.1016/j.drup.2025.101207","url":null,"abstract":"<div><h3>Background</h3><div>B7-H3 is a promising target for cancer therapy, notably in prostate cancer (PCa), particularly in metastatic, castration-resistant PCa (mCRPC). With the development of B7-H3-targeted therapies, there is a need for a rapid, reliable, and cost-effective method to detect and monitor B7-H3 expression. Leveraging their abundance and stability, we developed a liquid biopsy assay using extracellular vesicles (EVs) for this purpose.</div></div><div><h3>Methods</h3><div>B7-H3⁺ EVs were isolated using a B7-H3 antibody-mediated, click chemistry-based enrichment method. Antibodies were conjugated to methyltetrazine-grafted microbeads. EVs were isolated from 100 µL of plasma from metastatic, castration-sensitive PCa (mCSPC) (n = 43) and mCRPC (n = 103) patients and quantified using RT-qPCR of <em>ACTB</em>. Measurements were compared with the patient's disease status over time.</div></div><div><h3>Results</h3><div>The assay detected higher B7-H3⁺ EVs in mCRPC than mCSPC and increased when mCSPC transitioned to mCRPC. Elevated B7-H3⁺ EVs were associated with lower overall survival (Hazard ratio (HR) 2.19, <em>p</em> = 0.01). In patients with serial plasma samples, B7-H3⁺ EV levels reflected treatment response and disease progression.</div></div><div><h3>Conclusions</h3><div>This B7-H3⁺ EV assay represents a significant advancement in utilizing tumor-derived EVs for a non-invasive, quantitative, and consistent real-time measurement of B7-H3. This assay warrants further development as a companion diagnostic for B7-H3 targeted therapies in PCa and other conditions.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101207"},"PeriodicalIF":15.8,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143217855","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":"Dynamic evolution of KPC-230-mediated resistance to ceftazidime-avibactam during the treatment of carbapenem-resistant Klebsiella pnenmoniae","authors":"Xi Li ,&nbsp;Longjie Zhou ,&nbsp;Huaqiong Huang","doi":"10.1016/j.drup.2025.101205","DOIUrl":"10.1016/j.drup.2025.101205","url":null,"abstract":"<div><div>The molecular mechanisms driving the development of KPC-230-mediated resistance to ceftazidime-avibactam during treatment of carbapenem-resistant <em>Klebsiella pneumoniae</em> infection was elucidated by analyzing specimens collected from a patient, including one <em>bla</em>_KPC-230-positive and three <em>bla</em>_KPC-2-positive <em>Klebsiella pnenmoniae</em> isolates<em>.</em></div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101205"},"PeriodicalIF":15.8,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143076041","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":"Global dissemination of Klebsiella pneumoniae in surface waters: Genomic insights into drug resistance, virulence, and clinical relevance","authors":"Damian Rolbiecki ,&nbsp;Edyta Kiedrzyńska ,&nbsp;Małgorzata Czatzkowska ,&nbsp;Marcin Kiedrzyński ,&nbsp;Ewa Korzeniewska ,&nbsp;Monika Harnisz","doi":"10.1016/j.drup.2025.101204","DOIUrl":"10.1016/j.drup.2025.101204","url":null,"abstract":"<div><div>The aquatic environment is a major pathway for the spread of antibiotic resistance (AR) among microorganisms. Among these, <em>Klebsiella pneumoniae</em> reveals high genome plasticity, adaptability, and the ability to colonize humans, animals, and the natural environment, awarding it a significant role in the spread of AR. This work presents an in-depth analysis of the whole sequences of 149 <em>K. pneumoniae</em> genomes isolated from surface waters available in databases. The sequences were obtained from 20 countries in five continents. The analyses showed a high genomic diversity of isolates, classifying them into 94 unique sequence types. The isolates carried numerous virulence and drug resistance determinants in their genomes, including genes for carbapenem and colistin resistance. The critical resistance genes were located on plasmids, indicating their high mobility and ease of access in water environments. Sublineage 258 members, in particular ST11, have been identified as important carriers of both important drug resistance determinants and key virulence factors, thus posing a substantial threat to human health. Our analysis revealed the direct transmission of drug-resistant and virulent clinical strains to the natural environment, highlighting the role of <em>K. pneumoniae</em> in the dissemination of drug resistance within the \"One Health\" framework. Surface waters represent an environment conducive to the spread and evolution of drug resistance, and <em>K. pneumoniae</em> plays a significant role in this process by providing clinically-significant antibiotic resistance genes to environmental recipients.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101204"},"PeriodicalIF":15.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143030248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Osmotic stress influences microtubule drug response via WNK1 kinase signaling","authors":"Ana Monfort-Vengut ,&nbsp;Natalia Sanz-Gómez ,&nbsp;Sandra Ballesteros-Sánchez ,&nbsp;Beatriz Ortigosa ,&nbsp;Aitana Cambón ,&nbsp;Maria Ramos ,&nbsp;Ángela Montes-San Lorenzo ,&nbsp;María Escribano-Cebrián ,&nbsp;Juan Manuel Rosa-Rosa ,&nbsp;Joaquín Martínez-López ,&nbsp;Ricardo Sánchez-Prieto ,&nbsp;Rocío Sotillo ,&nbsp;Guillermo de Cárcer","doi":"10.1016/j.drup.2025.101203","DOIUrl":"10.1016/j.drup.2025.101203","url":null,"abstract":"<div><div>Ion homeostasis is critical for numerous cellular processes, and disturbances in ionic balance underlie diverse pathological conditions, including cancer progression. Targeting ion homeostasis is even considered as a strategy to treat cancer. However, very little is known about how ion homeostasis may influence anticancer drug response. In a genome-wide CRISPR-Cas9 resistance drug screen, we identified and validated the master osmostress regulator WNK1 kinase as a modulator of the response to the mitotic inhibitor rigosertib. Osmotic stress and WNK1 inactivation lead to an altered response not only to rigosertib treatment but also to other microtubule-related drugs, minimizing the prototypical mitotic arrest produced by these compounds. This effect is due to an alteration in microtubule stability and polymerization dynamics, likely maintained by fluctuations in intracellular molecular crowding upon WNK1 inactivation. This promotes resistance to microtubule depolymerizing compounds, and increased sensitivity to microtubule stabilizing drugs. In summary, our data proposes WNK1 osmoregulation activity as an important modulator for microtubule-associated chemotherapy response.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101203"},"PeriodicalIF":15.8,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035184","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":"Peptide-based PET/CT imaging visualizes PD-L1-driven radioresistance in glioblastoma","authors":"Yong Wang ,&nbsp;Zhiguo Liu ,&nbsp;Yang Li ,&nbsp;Kelin Wang ,&nbsp;Chunhui Yuan ,&nbsp;Jian Shi ,&nbsp;Jiazhong Ren ,&nbsp;Shijie Wang ,&nbsp;Jinping Wang ,&nbsp;Miaoqing Zhao ,&nbsp;Man Hu","doi":"10.1016/j.drup.2025.101202","DOIUrl":"10.1016/j.drup.2025.101202","url":null,"abstract":"<div><div>Radioresistance remains a great challenge for radiotherapy in the treatment of glioblastoma (GBM). PD-L1 expression is a key contributor to radioresistance and immune escape in GBM. The lack of effective methods to monitor the change of PD-L1 during radiotherapy in patients limits timely intervention and management of the resistance. Here, we developed a novel peptide tracer [¹⁸F]AlF-NOTA-PCP2 for PET/CT to visualize the changes of PD-L1 expression in response to radiotherapy, revealing PD-L1-driven radioresistance in GBM. The [¹⁸F]AlF-NOTA-PCP2 demonstrated high specificity and binding affinity to PD-L1 <em>in vitro.</em> The uptake of [¹⁸F]AlF-NOTA-PCP2 on PET/CT showed a strong positive correlation with PD-L1 expression by immunohistochemistry (IHC) (<em>R</em>² = 0.861, <em>P</em> &lt; 0.001) in GBM xenograft tumors. The radiotracer uptake in PD-L1-positive tumors significantly increased post-radiotherapy (21.25 ± 0.91 % vs. 25.12 ± 0.82 %, <em>P</em> = 0.008), aligning with the radioresistance observed in these tumors. <em>In vitro</em> studies revealed that PD-L1-driven radioresistance by enhancing DNA damage repair through upregulation of RAD51 after activation of the PI3K-Akt pathway in cells. Preliminary clinical application in a radiotherapy-treated GBM patient demonstrated the ability to monitor PD-L1 dynamics, supporting its potential for clinical translation. Collectively, this peptide-based small molecule PET/CT radiotracers offer a noninvasive, real-time, and quantitative method to dynamically visualize PD-L1-driven radioresistance in GBM. It could serve as a potential radiotracer for facilitating patient stratification, adjusting radiotherapy regimens, and guiding personalized immunotherapy strategies.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101202"},"PeriodicalIF":15.8,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990351","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organoid models of drug resistant gastric adenosquamous carcinoma: Recapitulating tumor features and refining precision treatment","authors":"Kuan Li ,&nbsp;Wenchao Li ,&nbsp;Shuying Fu ,&nbsp;Chen Wang ,&nbsp;Kexin Wang ,&nbsp;Huan Yang ,&nbsp;Yumei Xian ,&nbsp;Tengfei Hao ,&nbsp;Shiwei Zhang ,&nbsp;Tianshun Gao ,&nbsp;Jie Zhou ,&nbsp;Jia Li ,&nbsp;Changhua Zhang ,&nbsp;Wei Chen ,&nbsp;Leli Zeng ,&nbsp;Yulong He","doi":"10.1016/j.drup.2025.101201","DOIUrl":"10.1016/j.drup.2025.101201","url":null,"abstract":"<div><div>Organoids were successfully established from primary tumor and its metastatic lymph nodes of a patient. These organoids faithfully replicated tumor pathology and genetic characteristics. Organoid-based drug screening was conducted, which revealed significant difference in sensitivity to drugs between organoids dervived from primary tumor versus metastatic lymph nodes. The results guided clinical decisions for personalized treatment for the patient. This approach provides an insightful strategy for advancing treatment for gastric cancer.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101201"},"PeriodicalIF":15.8,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967274","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":"Exploring treatment-driven subclonal evolution of prognostic triple biomarkers: Dual gene fusions and chimeric RNA variants in novel subtypes of acute myeloid leukemia patients with KMT2A rearrangement","authors":"Yi Xu ,&nbsp;Shengwen Calvin Li ,&nbsp;Jeffrey Xiao ,&nbsp;Qian Liu ,&nbsp;Durga Cherukuri ,&nbsp;Yan Liu ,&nbsp;Saied Mirshahidi ,&nbsp;Jane Xu ,&nbsp;Xuelian Chen ,&nbsp;Dadrastoussi Homa ,&nbsp;Julian Olea ,&nbsp;Kaijin Wu ,&nbsp;Kevin R. Kelly ,&nbsp;Fengzhu Sun ,&nbsp;Ruihao Huang ,&nbsp;Xiaoqi Wang ,&nbsp;Qin Wen ,&nbsp;Xi Zhang ,&nbsp;Cristina M. Ghiuzeli ,&nbsp;Esther Chong ,&nbsp;Jiang F. Zhong","doi":"10.1016/j.drup.2024.101199","DOIUrl":"10.1016/j.drup.2024.101199","url":null,"abstract":"<div><div>Chromosomal rearrangements (CR) initiate leukemogenesis in approximately 50 % of acute myeloid leukemia (AML) patients; however, limited targeted therapies exist due to a lack of accurate molecular and genetic biomarkers of refractory mechanisms during treatment. Here, we investigated the pathological landscape of treatment resistance and relapse in 16 CR-AML patients by monitoring cytogenetic, RNAseq, and genome-wide changes among newly diagnosed, refractory, and relapsed AML. First, in FISH-diagnosed KMT2A (MLL gene, 11q23)/AFDN (AF6, 6q27)-rearrangement, RNA-sequencing identified an unknown CCDC32 (15q15.1)/CBX3 (7p15.2) gene fusion in both newly diagnosed and relapsed samples, which is previously unknown in KMT2A/AFDN-rearranged AML patients. Second, the unreported CCDC32/CBX3 gene fusion significantly affected the expression of wild-type genes of both CCDC32 (essential for embryonic development) and CBX3 (an oncogene for solid tumors) during the relapse, as demonstrated by Quantitative PCR analyses. Third, we further confirmed the existence of triple biomarkers - KMT2A/AFDN (AF6, 6q27) rearrangement, the unknown CCDC32 (15q15.1)/CBX3 (7p15.2) gene fusion and chimeric RNA variants (treatment-resistant leukemic blasts harboring distinct breakpoints) in a 21-year-old male patient of rapid relapsed/refractory AML. Most intriguingly, in this work regarding 16 patients, patients 7 and 20 initially showed the KMT2A/AFDN gene fusion; upon relapse, patient 20 did not show this fusion. On the other hand, patient 7 retained the KMT2A/AFDN fusion at diagnosis and during the relapse, only identified by PCR and Sanger's Sequencing, not by cytogenetics. Interestingly, the chimeric CCDC32/CBX3 gene fusion persisted in the 21-year-old male patient over the diagnostic and relapse phases. Most intriguingly, the overexpression of CCDC32/CBX3 fusion gene in AML patient-specific MV4-11 cells confirms the functional validation, providing experimental evidence of the biological impact of the CCDC32/CBX3 fusion on AML pathogenesis and treatment resistance by promoting cell cycle progression, a mechanism through which AML evolves to become treatment-resistant. All these might exhort differential resistance to treatment. Thus, we found that prognostic and predictive triple biomarkers - KRAS mutated, dual fusions (KMT2A/AFDN, CCDC32/CBX3), and chimeric variants - might evolve with a potential oncogenic role of subclonal evolution for poor clinical outcomes.</div></div>","PeriodicalId":51022,"journal":{"name":"Drug Resistance Updates","volume":"79 ","pages":"Article 101199"},"PeriodicalIF":15.8,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142990322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}