Cancers doi: 10.20517/cdr.2026.54

Authors: Aurélie H. Benfield,Reuben S. E. Young,Grégoire J. B. Philippe,Nicholas D. Condon,Nicolau Barbosa Palma Filho,Helmut Schaider,Stephen J. Blanksby,Sónia Troeira Henriques

Aim: Cancer drug resistance is driven by dynamic, systems-level adaptations, including cellular state transitions, epigenetic reprogramming, metabolic rewiring, and proteome remodelling. Lipid metabolic reprogramming is increasingly recognised as a contributor to resistance through alterations in the membrane composition and has been hypothesised to promote resistance by increasing membrane rigidity and limiting drug permeability. Here we tested this hypothesis in melanoma using a cell state-resolved multi-omics approach.

Methods: We combined lipidomics, surface-resolved phospholipid profiling, live-cell biophysical measurements, and whole-cell proteomics to characterise plasma membrane composition and function across drug-naïve, drug-tolerant persister, and permanently drug-resistant states in BRAF^V600E metastatic melanoma cells treated with dabrafenib.

Results: Lipidomic analyses revealed membrane remodelling, particularly in the drug-tolerant state, including altered fatty acid chain unsaturation, and increased cholesterol (Chol) and sphingomyelin levels. All cell states retained surface exposure of negatively charged phosphatidylserine and phosphatidylinositol. Despite compositional changes typically associated with membrane rigidification, plasma membrane fluidity and tension remain conserved across all resistance states. Proteomic analysis further revealed coordinated regulation of lipid metabolic pathways, including Chol homeostasis and sphingolipid turnover, indicating that lipid-metabolic adaptation supports survival under drug pressure without substantially altering membrane biophysical properties.

Conclusion: These findings show that lipid metabolic rewiring supports drug tolerance while conserving core membrane features. By resolving resistance-associated changes across both molecular and biophysical layers, this study identifies shared plasma membrane features and vulnerabilities across heterogeneous melanoma cell populations, supporting the application of membrane-active therapeutic agents and of combination strategies targeting lipid-metabolic adaptations to delay or prevent resistance.

Cancers doi: 10.20517/cdr.2025.229

Authors: Giulia Ambrosini,Elisa Dalla Pozza,Ilaria Cristanini,Sara Vinco,Enrica Cappellozza,Barbara Cisterna,Claudio Laquatra,Andrea Rasola,Emanuela Bottani,Ilaria Dando

Aim: Cancer stem cells (CSCs) in pancreatic ductal adenocarcinoma (PDAC) display high metabolic plasticity, supporting tumor aggressiveness and therapeutic resistance. Here, we investigated the role of the mitochondrial chaperone TRAP1 in regulating mitochondrial architecture, metabolism, and adhesion in CSCs.

Methods: We studied an in vitro model of CSCs using Panc1 cells and the corresponding stable TRAP1-knockout cells (TRAP1-KO). Molecular techniques used were quantitative polymerase chain reaction (qPCR), Western blot, transmission electron microscopy, and Seahorse technology.

Results: CSCs showed increased TRAP1 expression after 2 weeks of culture, reflecting a preferential metabolic shift toward glycolysis. TRAP1 deletion impaired the ability of CSCs to form compact spheroids without altering canonical CSC traits, such as reduced proliferation, increased stem marker expression, and enhanced chemoresistance. We demonstrate that TRAP1 deletion increases CDH1, an effect that was reversed by succinate supplementation, indicating that the TRAP1–succinate-CDH1 axis controls adhesion-related properties. Ultrastructural analyses revealed profound mitochondrial remodeling in the absence of TRAP1: parental cells displayed enlarged, elongated mitochondria with wider cristae, whereas CSCs developed fragmented mitochondria with thinner cristae and tighter crista junctions. These alterations were closely associated with the differential regulation of mitochondrial fission factor (MFF). Functionally, loss of TRAP1 enhanced oxidative phosphorylation, leading to increased mitochondrial adenosine triphosphate (ATP) production, elevated maximal respiration, and reduced proton leak.

Conclusion: Collectively, these findings identify TRAP1 as a critical regulator of mitochondrial organization, respiratory efficiency, and CDH1-mediated adhesion in PDAC CSCs, highlighting metabolic and structural vulnerabilities that may be exploited therapeutically to destabilize CSC homeostasis and enhance treatment response.

Cancers doi: 10.20517/cdr.2025.151

Authors: Jacob S. Roth,Hui Guo,Lu Chen,Min Shen,Omotola Gbadegesin,Robert W. Robey,Michael M. Gottesman,Matthew D. Hall

Aim: Antibody-drug conjugates (ADCs) feature an antibody recognizing a specific protein joined to a potent toxic payload. Numerous ADCs have received U.S. Food and Drug Administration (FDA) approval; however, clinical resistance arises. Resistance mechanisms include decreased expression or mutation of the antibody target, impaired payload release, or increased expression of adenosine triphosphate (ATP)-binding cassette (ABC) efflux transporters associated with multidrug resistance. We therefore sought to characterize the interactions of ABC multidrug transporters with ADC payloads.

Methods: We performed a high-throughput screen with 27 common ADC payloads using cell lines expressing ABC transporters P-glycoprotein [P-gp, encoded by ABC subfamily B member 1 (ABCB1)] or ABC subfamily B member G2 (ABCG2, encoded by ABCG2). Confirmatory assays were also performed using cells transfected to express P-gp, ABCG2, or multidrug resistance-associated protein 1 (MRP1, encoded by ABCC1).

Results: Several commonly used ADC payloads were substrates of P-gp, including calicheamicin γ1, monomethyl auristatin E, mertansine (DM1), and ravtansine (DM4). All the pyrrolobenzodiazepines tested - SJG136, SGD-1882, SG2057, and SG3199 - were substrates of P-gp, ABCG2, and MRP1. The modified anthracyclines nemorubicin and its metabolite PNU-159682 were poorly transported by both ABCB1 and ABCG2 and displayed nanomolar to picomolar toxicity. Further, we found that the efficacy of the FDA-approved ADC mirvetuximab soravtansine, with DM4 as the toxic payload, was decreased in cell lines expressing P-gp. In contrast, Duocarmycin DM and PNU-159682 were exquisitely toxic to a panel of 99 cancer cell lines of varying origins.

Conclusion: Several commonly used ADC payloads can be transported by ABC transporters, potentially leading to transporter-mediated drug resistance in patients. Future ADCs should be developed using payloads that are not ABC transporter substrates.

Cancers doi: 10.20517/cdr.2025.175

Authors: Bárbara Polónia,Cristina P. R. Xavier,Sara Peixoto da Silva,Chiara Riganti,M. Helena Vasconcelos

Aim: Non-small cell lung cancer (NSCLC) represents most lung cancer cases and remains associated with poor outcomes, mainly due to multidrug resistance (MDR). Extracellular vesicles (EVs) are crucial for intercellular communication and significantly influence chemotherapy resistance. This study aimed to characterize the EVs proteome of drug-sensitive and MDR NSCLC cell lines to identify therapeutic targets to counteract MDR.

Methods: EVs derived from NSCLC cells were isolated by ultracentrifugation and analyzed for size by nanoparticle tracking analysis, for morphology by transmission electron microscopy, and for EVs markers by Western blotting (WB). Proteomic profiling was performed using liquid chromatography-mass spectrometry (LC-MS), followed by WB validation of relevant proteins. Cell growth and viability were assessed using sulforhodamine B or CellTiter-Glo assays. P-glycoprotein [P-gp, also known as ABCB1: adenosine triphosphate (ATP)-binding cassette subfamily B member 1] activity was determined by rhodamine-123 accumulation assay. SRC-related signaling was investigated by WB.

Results: EVs from the multidrug resistant (MDR) derivative of NCI-H460, a human NSCLC cell line, displayed nine up- and eight down-regulated proteins compared with the drug-sensitive parental cells, including reduced SRC. WB results showed higher phosphorylated form of SRC (p-SRC) expression in MDR cells than in sensitive cells. In contrast, EVs from both cell lines had similar expression levels, suggesting selective intracellular retention in MDR cells. The SRC inhibitor bosutinib potentiated the activity of chemotherapeutics that are P-gp substrates in 2D and in 3D spheroids, without affecting the viability of the human lung fibroblast cell line MRC-5. Moreover, bosutinib reduced P-gp activity, likely by downregulating of phosphorylated caveolin-1.

Conclusion: These findings show reduced selective packaging of p-SRC into EVs shed by MDR cells (MDR-EVs), suggesting an important role for this protein in the MDR phenotype and its potential as a molecular target. Bosutinib, an SRC inhibitor, might be useful as a chemosensitizer of MDR cells.

Cancers doi: 10.20517/cdr.2025.191

Authors: Maël Heiblig,Charles Dumontet,Marie-Aimée Dronne,Xavier Thomas,Adriana Plesa,Emeline Perrial,Jérôme Guitton,Christelle Machon

Aim: Resistance to frontline intensive chemotherapy remains a major clinical challenge in acute myeloid leukemia (AML). Currently, refractory AML is mostly observed in certain genotypes. In in vitro experiments, primary resistance in AML has been associated with nucleotide metabolism. However, the relationship between in vivo nucleotide metabolism, genotype, and the occurrence of complete remission (CR) remains largely unexplored. We aimed to investigate the potential association between in vivo nucleotide pools at AML diagnosis, genotype, and the efficacy of frontline intensive chemotherapy.

Methods: In this prospective pilot study, we quantified the intracellular nucleotide pools in peripheral blood (PBMC) and bone marrow mononuclear cells (BMMC) from 70 AML patients at diagnosis. Nucleotide levels were compared depending on genotype data and the occurrence of CR after the frontline intensive chemotherapy.

Results: No relationship was observed between nucleotide levels and genotype. Specific alterations of certain nucleotide levels in cells from patients who did not achieve CR were identified: elevated guanosine triphosphate (GTP) levels in BMMC and uridine monophosphate (UMP) levels in PBMC, as well as reduced adenosine monophosphate (AMP) levels and energy ratios [AMP/adenosine triphosphate (ATP), AMP + adenosine diphosphate (ADP)/ATP] in PBMC. These results may suggest impaired activity of enzymes such as UMP/cytidine monophosphate (CMP) kinase and reduced AMP-activated protein kinase (AMPK) activation in patients who did not achieve CR.

Conclusion: Our study provides the first in vivo data linking specific alterations in intracellular nucleotide levels to the efficacy of the frontline intensive chemotherapy in AML. These findings offer a novel perspective on the role of nucleotide metabolism in the primary resistance in frontline intensive chemotherapy.

Cancers doi: 10.20517/cdr.2025.195

Authors: Pilar Eroles,María Teresa Dawid de Vera,Víctor Lago

Antibody-drug conjugates (ADCs) targeting trophoblast cell-surface antigen 2 (TROP2) have emerged as a promising therapeutic strategy for the treatment of triple-negative breast cancer (TNBC) and ovarian carcinoma, two malignancies characterized by poor prognosis and limited therapeutic options. ADCs are complex molecules that combine the specificity of monoclonal antibodies with the cytotoxic potency of chemotherapeutic agents, enabling selective delivery of drugs to tumor cells while minimizing systemic toxicity. Recent advances in ADC technology have led to the development of several TROP2-targeting agents, including sacituzumab govitecan and datopotamab deruxtecan, which have demonstrated significant efficacy and acceptable safety in patients with advanced or treatment-resistant TNBC and ovarian carcinoma. Clinical trials have reported improvements in progression-free and overall survival, as well as objective response rates, compared to standard therapies. However, emerging evidence indicates that both primary and acquired resistance mechanisms may limit the long-term efficacy of these agents. Current research efforts are focused on elucidating these resistance pathways, optimizing combination strategies with immunotherapy and targeted agents, and expanding the application of TROP2-targeting ADCs to other tumor types. The integration of biomarker-driven patient selection and next-generation ADC technologies offers new opportunities to overcome resistance and enhance clinical benefit. This review provides a comprehensive overview of the development, clinical implementation, and resistance mechanisms of TROP2-targeting ADCs in TNBC and ovarian carcinoma, underscoring their potential to reshape the therapeutic landscape of these challenging cancers.

Cancers doi: 10.20517/cdr.2025.231

Authors: Birou Lai,Chang Xu,Siyi Lai,Mo Zhou,Hesheng Kong,Eryan Kong,Badrul Hisham Yahaya

Lung cancer represents the most prevalent and lethal malignancy worldwide. Although tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) demonstrate clinical efficacy, the emergence of resistance remains a major therapeutic obstacle. This review comprehensively examines how six key post-translational modifications (PTMs) of EGFR - phosphorylation, palmitoylation, ubiquitination, glycosylation, acetylation, and S-nitrosylation - collectively govern its signaling dynamics, protein turnover, and subcellular trafficking. Based on this mechanistic framework, we propose a novel classification of resistance subtypes: membrane-retained, degradation-evading, nuclear-localized, and mitochondrial-localized EGFR, each defined by distinct PTM signatures and spatial localization. Furthermore, we analyze the intricate crosstalk among these PTMs, revealing hierarchical and often cooperative relationships that ultimately determine the fate and function of EGFR. Our analysis suggests that targeting specific spatial PTM hubs or their interactive networks, rather than EGFR alone, offers a promising strategy to overcome resistance. We also emphasize the need to integrate multi-PTM profiling with spatial proteomics to inform precision combination therapies. This work proposes a shift in the therapeutic paradigm from mere kinase inhibition toward reprogramming the pathological PTM network underlying resistant lung cancer.

Cancers doi: 10.20517/cdr.2025.196

Authors: Lingna Wang,Yufei Mao,Yu Dong,Manqi Tan,Xingyu Wang,Zhaobo Liu,Chenyao Nie,Shu Xing,Meng Li,Haitao Yuan,Bing Wang

Aim: Multidrug resistance (MDR) often arises from lysosomal sequestration of chemotherapeutics. This study aims to design and evaluate lysosome-targeting membrane-intercalating conjugated oligoelectrolytes (MICOEs) for their potential to reverse MDR via dual-mode lysosomal membrane disruption, and to identify the most effective candidate.

Methods: Three MICOEs featuring a pyridothiadiazole-thienothiophene-pyridothiadiazole (PTTP) conjugated backbone with quaternary ammonium-terminated 4-, 6-, and 8-carbon alkyl chains at both ends (PTTP-DC4, PTTP-DC6, PTTP-DC8) were synthesized and characterized. Their photophysical properties, cellular uptake, and sublocalization were assessed in doxorubicin (DOX)-resistant Michigan Cancer Foundation-7/adriamycin-resistant (MCF-7/ADR) cells. Lysosomal integrity and contents release were evaluated via acridine orange and cathepsin B assays. Proteomic analysis was performed to uncover mechanisms. The combinational effect of PTTP-DC6 and DOX was tested in drug-resistant two-dimensional (2D) and three-dimensional (3D) cell models.

Results: Among PTTP-DCns (where n = 4, 6, and 8, corresponding to PTTP-DC4, PTTP-DC6, and PTTP-DC8), PTTP-DC6 showed optimal lysosomal accumulation and induced lysosomal membrane permeabilization (LMP) through both physical membrane interaction and light-triggered reactive oxygen species generation. Proteomic analysis revealed significant enrichment of pathways associated with oxidative stress and lysosomal dysfunction. Pretreatment with PTTP-DC6 at low doses, particularly under mild light irradiation, significantly enhanced DOX sensitivity in resistant 2D monolayers and 3D spheroid models.

Conclusion: PTTP-DC6 overcomes MDR by dual-mode LMP induction, providing a simple strategy to resensitize resistant cancers to conventional chemotherapy.

Cancers doi: 10.20517/cdr.2025.215

Authors: Wanyi Xia,Yulong Zhang,Juanzhi Zhao,Xiaoli Tan,Shaolong Ju,Wei Zou,Chaoqun Chen,Chunwei Li,Yanghua Xu,Yingming Peng,Shengqiao Li

Malignant pleural mesothelioma (MPM) remains one of the most aggressive thoracic malignancies, characterized by profound resistance to conventional modalities such as surgery, chemotherapy, and radiotherapy, resulting in persistently poor survival outcomes. The advent of immune checkpoint inhibitors (ICIs) has fundamentally reshaped the therapeutic landscape of MPM. Notably, dual programmed cell death protein 1 (PD-1)/cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade has demonstrated superior efficacy over monotherapy in multiple phase I/II trials and has been established as a novel first-line standard of care. Nevertheless, the high incidence of resistance continues to pose a major clinical challenge. This therapeutic bottleneck is largely attributed to the unique biology of MPM, including a profoundly immunosuppressive tumor microenvironment, aberrantly activated signaling pathways, and complex metabolic reprogramming, which together form a multilayered defense network against immune attack. In response to this intricate resistance architecture, recent research efforts have increasingly focused on the development of precision combination strategies. By rationally integrating ICIs with anti-angiogenic agents, chemotherapy, metabolic modulators, and next-generation cellular immunotherapies [e.g., chimeric antigen receptor T cells (CAR-T), chimeric antigen receptor-natural killer (CAR-NK)], these approaches aim to dismantle immune evasion barriers and reinvigorate antitumor immunity. Concurrently, the discovery of novel biomarkers and their integration with multi-omics data are enabling more precise patient stratification, signaling the advent of an era of personalized immunotherapy for MPM. This review provides a systematic synthesis of the latest clinical advances and fundamental breakthroughs in MPM immunotherapy, with a particular focus on dissecting the multifactorial mechanisms underlying therapeutic resistance. Its core contribution lies in constructing a forward-looking framework for next-generation treatment strategies. It critically evaluates the translational potential of emerging approaches, including arginine deprivation therapy for argininosuccinate synthase 1 (ASS1)-deficient tumors, CAR-T cells, T-cell receptor fusion constructs, and oncolytic virotherapy. By integrating these innovative modalities with biomarker-guided patient selection, this review delineates a roadmap for transitioning MPM management from empirical therapy toward precision immuno-oncology, with the ultimate goal of achieving durable disease control in this challenging malignancy.

Cancers doi: 10.20517/cdr.2025.213

Authors: Yayu Chen,Zhishuang Ye,Yanping Wang,Shanlan Liang,Daniel Xin Zhang

Non-coding RNAs (ncRNAs) have emerged as key regulators of cancer–immune crosstalk, especially in an era when immune checkpoint inhibitors and other immunomodulatory therapies are reshaping the cancer treatment landscape. Accumulating evidence continues to indicate that ncRNAs, including microRNAs, long non-coding RNAs and circular RNAs, critically connect oncological signaling with immune interactions, thereby influencing clinical outcomes. In this review, we summarize how ncRNAs modulate key immune checkpoint axes, particularly programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4). We also discuss ncRNA networks that are actively involved in modern cancer immunotherapies, such as T cell–based therapies, macrophage and dendritic cell engineering, cytokine therapies, cancer vaccines and oncolytic viruses. Building on these mechanistic insights, we outline the potential of ncRNAs as biomarkers for predicting response and prognosis, as future therapeutic targets to improve and enhance immunotherapy combinations, along with key barriers in the field and emerging solutions. Altogether, the evidence not only highlights ncRNAs as rising stars in precision immuno-oncology, but also motivates future opportunities to incorporate ncRNAs into clinical consideration.

Cancers doi: 10.20517/cdr.2025.223

Authors: Wonseok Choi,Min-Hyeok Jang,Chulhong Kim,Eun-Yeong Park

The glymphatic system in the brain controls the cerebrospinal fluid (CSF) circulation and metabolic waste clearance, which is crucial for understanding the mechanisms and therapeutic opportunities of various brain pathologies. With the rapidly growing interest in its relationship with neurodegenerative conditions, including Alzheimer’s disease, its underlying processes are still not fully understood and remain under active investigation. A representative finding is that the glymphatic flow is passively driven by factors such as vascular pulsation, and studies have been conducted to modulate the glymphatic system using external stimuli to enhance waste clearance or to leverage CSF pathways for delivering chemotherapeutic agents. Particularly, glymphatic flow modulation holds great potential for improving drug delivery to the brain via intrathecal administration as an alternative to conventional systemic delivery, which is restricted by the blood-brain barrier (BBB). This review focuses on ultrasound (US) techniques for glymphatic system modulation, with the aim of augmenting glymphatic flow and ultimately improving drug delivery for brain cancer therapy. Given the limited number of cancer-related studies in the field, we comprehensively review US-based glymphatic modulation research to date and identify their implications and future opportunities for brain cancer applications.

Cancers doi: 10.20517/cdr.2026.09

Authors: Li Hu,Yaxin Zhang,Boyang Wang,Qian Liu,Feiyang Qi,Huimin Liu,Qinghua Li,Zhiqing Zhao,Haijie Liang,Xingyu Liu,Zhiye Du,Jichuan Wang

Aim: Osteosarcoma remains aggressive with poor prognosis, particularly in chemotherapy-resistant cases. This study aimed to characterize transcriptional features of chemoresistant osteosarcoma cells, establish a prognostic resistance signature, and identify therapeutic vulnerabilities.

Methods: Single-cell RNA sequencing (scRNA-seq) was performed on paired pre- and post-neoadjuvant chemotherapy (NAC) specimens from three patients (6 samples; 16,272 cells). Resistance trajectories were reconstructed using Monocle 3 pseudotime analysis. A nine-gene resistance score was validated in the Peking University People’s Hospital (PKPH) bulk RNA-seq cohort (n = 70) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database (n = 87), with drug sensitivities predicted via oncoPredict.

Results: Chemotherapy reduced the malignant cell fraction but triggered expansion of cancer-associated fibroblasts and endothelial cells, creating a stromal-dominant, immune-sparse residual niche. Surviving tumor cells upregulated a nine-gene module along the resistance trajectory: KCNMA1, KIF21A, MIR181A1HG, RPS27, PDPN, ADIRF, PRELP, PHEX, and COL9A2. In an independent unpaired scRNA-seq cohort (two pre- and three post-chemotherapy samples), this signature remained associated with features of chemotherapy resistance. Higher scores correlated with poorer histopathologic response (r = -0.35, P = 0.006) and shorter progression-free survival [PKPH: hazard ratio (HR) = 2.4, 95% confidence interval (CI) 1.2-4.8, P = 0.01; TARGET: HR = 2.1, 95%CI 1.1-4.0, P = 0.02]. Of 198 compounds screened, only Pictilisib, a phosphoinositide 3-kinase (PI3K) inhibitor, showed lower predicted IC50 in the high-score subset across both datasets. However, the paired discovery cohort warrant further validation.

Conclusion: Our paired scRNA-seq approach identifies a nine-gene signature linking pre-treatment tumor biology to NAC response and outcome. The enhanced Pictilisib sensitivity in chemoresistant tumors positions PI3K blockade as a strategy meriting prospective testing in refractory osteosarcoma.

Cancers doi: 10.20517/cdr.2025.207

Authors: Yiyang Lin,Jianliang Shen

Immune-checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have substantially improved outcomes for patients with multiple cancer types; however, primary (intrinsic) resistance remains common and limits durable responses. Mechanistically, such resistance can arise from impaired interferon-γ signaling (including Janus kinases-signal transducer and activator of transcription dysfunction), tumor-intrinsic oncogenic pathway alterations [e.g., phosphatase and tensin homolog (PTEN) loss with downstream phosphoinositide 3-kinase/protein kinase B hyperactivation and Wnt/β-catenin-associated immune escape], and tumor-extrinsic immunosuppression mediated by PD-L1-upregulated suppressive myeloid populations such as myeloid-derived suppressor cells. These pathways converge on reduced T-cell effector function, compromised immune recognition, and reinforcement of an immunosuppressive tumor microenvironment (TME), collectively diminishing the clinical benefit of PD-1/PD-L1 blockade. In this review, we synthesize current evidence on primary (intrinsic) resistance to PD-1/PD-L1 blockade and discuss how nanomaterial-enabled interventions can be mechanistically matched to these resistance determinants. The nanotechnology-based therapeutic strategies were classified as four categories: (i) modulation of resistance-associated signaling pathways; (ii) direct blockade/interception of the PD-1/PD-L1 axis; (iii) immune-checkpoint gene silencing; and (iv) TME reprogramming.

Cancers doi: 10.20517/cdr.2025.203

Authors: Dileepkumar Veeragoni,Hindole Ghosh,Affan Ansari,Sangita Bhattacharyya,Ahraar Azaz,Ojaswitha Ommi,Obdulia Covarrubias-Zambrano,Leonhard H. F. Köhler,Justus F. Ködel,Ameer Hamza,Anup Kasi,Stefan H. Bossmann,Rainer Schobert,Bernhard Biersack,Prasad Dandawate

Aim: This study investigates the anticancer activity of naphthalene- and ferrocene-based 2-pyrazolines against colorectal cancer (CRC) cell lines and assesses their potential to overcome chemotherapy resistance.

Methods: Several 2-pyrazoline derivatives were synthesized and tested for anticancer activity across various cell lines, including p53 wild-type (WT) and knockout (KO) colon cancer cells and vinblastine-resistant KB-V1 cervix carcinoma cells. Compounds Clac10 (5c) and Clac12 (5e) were studied for their effects on colony and spheroid formation, cell cycle, and apoptosis. Molecular docking and cellular thermal shift assays explored their binding to histamine receptor H1 (HRH1). In vivo antitumor efficacy was tested on HCT116 xenografts in NSG mice.

Results: Compounds Clac10 and Clac12 significantly inhibited the proliferation of both p53 WT and KO colon cancer cells, as well as drug-resistant KB-V1 cells. When combined with 5-fluorouracil (5-FU), they showed synergistic antiproliferative effects in HCT and DLD1 cells. These compounds reduced colony and spheroid formation, induced cell cycle arrest, and promoted apoptosis by downregulating cyclin D1 and antiapoptotic proteins [B-cell lymphoma-extra large (Bcl-XL), B-cell lymphoma 2 (Bcl-2), myeloid cell leukemia 1 (Mcl-1)]. Molecular docking and thermal shift assays confirmed binding to HRH1, affecting histamine-induced extracellular signal-regulated kinase (ERK) and glycogen synthase kinase 3 beta (GSK3B) signaling. In vivo, Clac10 significantly reduced HCT116 xenograft growth, decreased Ki-67 and phosphorylated-glycogen synthase kinase 3 beta (p-GSK3B) levels, and increased cleaved caspase-3.

Conclusion: Naphthalene-based 2-pyrazoline compounds Clac10 and Clac12 showed a potent anticancer activity against colon cancer lines. They inhibit tumor growth by targeting HRH1 signaling, indicating potential as CRC therapies and resistance-overcoming agents. Further studies are needed to explore their clinical potential.

Cancers doi: 10.20517/cdr.2025.216

Authors: Erhan Da,Ronglan Zhu,Bin Xi,Liyang Zhang,Guodong Tang

Tumors are highly dynamic diseases characterized by significant heterogeneity. They consist of multiple cellular populations with distinct properties that respond differently to therapeutic pressure. This heterogeneity may arise from spatial variation across tumor regions (spatial heterogeneity) as well as from temporal changes during tumor evolution and treatment (temporal heterogeneity). As a consequence, drug-resistant subclones often emerge under therapy and contribute to treatment failure. Advances in single-cell and spatial multi-omics technologies enable precise quantification of tumor heterogeneity, supporting detailed investigation of how heterogeneity contributes to chemoresistance and informing the development of personalized therapeutic strategies. In this review, we summarize the evolutionary dynamics underlying the emergence of tumor drug resistance and examine the molecular mechanisms responsible for failure of targeted therapies. We highlight how advances in single-cell and spatial multi-omics have significantly improved our ability to elucidate these processes. We further suggest that addressing tumor drug resistance may require a shift from static, single-target approaches toward dynamic, biology-informed personalized strategies. Integrating high-resolution multi-omics monitoring with functional validation could enable identification of subclonal vulnerabilities, support adaptive treatment adjustment, and contribute to more durable clinical responses.

Cancers doi: 10.20517/cdr.2026.12

Authors: Lijun Li,Yanbin Zhao,Xinhong Shi,Xiaotian Guo,Xiaoxin Zhang,Guangrui Li,Qingwei Meng,Minghui Zhang,Mingzhu Yin

Recently, programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have achieved major breakthroughs in oncology, with 32 drugs approved over the past decade. This advancement has established immunotherapy as the fifth major antitumor modality following surgery, chemotherapy, radiotherapy, and targeted therapy. However, PD-1/PD-L1 inhibitors induce sustained responses in only a limited number of patients, and primary and acquired resistance remain critical challenges in clinical practice. As understanding of the complex crosstalk among cancer cells, the tumor microenvironment, and the host immune system deepens, numerous strategies to overcome PD-1/PD-L1 inhibitor resistance have been proposed. In this review, we examine the current development of PD-1/PD-L1 inhibitors, analyze global approval trends, and evaluate their monotherapy efficacy across various tumor types. As multi-target combination therapy is an essential strategy for overcoming resistance, we analyze key combination targets - such as vascular endothelial growth factor (VEGF), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte activation gene 3 (LAG-3) - and highlight the clinical success of novel dual-target regimens such as ivonescimab (PD-1/VEGF). Furthermore, we discuss potential approaches to overcoming resistance from both microenvironmental (e.g., targeting cancer-associated fibroblasts or utilizing antibody-drug conjugates) and macroenvironmental (e.g., modulating the microbiota or sex hormones) perspectives. This review provides a forward-looking framework for designing precision- and mechanism-driven combination therapies aimed at converting non-responders into responders.

Cancers doi: 10.20517/cdr.2026.80

Authors: Hongrui Liu,Liang Ma,Yixuan Wang,Yuheng Wang,Siyu Chen,Mingzhen Wang,Dingge Cao,Yi Chen,Wenzhe Si

The deubiquitinase PSMD14 (also known as RPN11 or POH1), a critical component of the JAB1/MPN/Mov34 metalloenzyme family, has emerged as a pivotal regulator of protein homeostasis through its deubiquitinating activity. While preclinical studies have extensively characterized PSMD14-mediated stabilization of oncogenic substrates involved in cell cycle progression, programmed cell death, metastasis, metabolic reprogramming, and immune evasion, a translational gap remains between these mechanistic insights and clinical application. This review synthesizes current evidence demonstrating that PSMD14 drives therapeutic resistance across multiple malignancies, including resistance to cisplatin, oxaliplatin, temozolomide, anlotinib, tamoxifen, and bortezomib by deubiquitinating and stabilizing key effectors such as E2F1, ALK2, IMPDH2, estrogen receptor α, and proteasomal components. Furthermore, we highlight the prognostic value of PSMD14 as a biomarker for overall survival and recurrence prediction in hepatocellular carcinoma, pancreatic cancer, lung cancer, and other malignancies, along with its emerging role in non-tumor conditions such as glucocorticoid-induced osteoporosis and post-cardiac arrest neurological outcomes. We critically evaluate the therapeutic landscape of PSMD14 inhibitors, from natural products (thiolutin) and synthetic agents (Capzimin, O-phenanthroline) to next-generation dual-target inhibitors, and discuss the clinical barriers to translation, including off-target toxicity, patient stratification, and optimal combination strategies. By integrating mechanistic discovery with biomarker development and inhibitor optimization, this review aims to lay a foundation for the future development of PSMD14-targeted therapeutic strategies.

Cancers doi: 10.20517/cdr.2025.210

Authors: Paola Verachi,Federica Francescangeli,Rosanna Dattilo,Alessandro Vici,Rachele Rossi,Elena Landolfo,Maria Laura De Angelis,Ann Zeuner

Fenretinide [N-(4-hydroxyphenyl) retinamide, 4-HPR] is a synthetic retinoid known for decades for its antitumor activity and favorable toxicological profile. In vitro and in vivo studies have demonstrated that fenretinide has broad-spectrum anticancer potential, eliciting multiple biological effects and acting as a multi-target compound that influences both tumor cells and the tumor microenvironment. However, the clinical application of fenretinide has been hampered by unfavorable physicochemical properties, such as poor solubility and low bioavailability, leading to highly variable outcomes in clinical studies. The development of novel fenretinide nanoformulations based on drug encapsulation in nanomicelles has helped overcome bioavailability limitations and improve anticancer efficacy in preclinical studies, thereby paving the way for new clinical opportunities. Moreover, recent studies have shown that fenretinide restrains the cancer stem cell compartment and promotes tumor cell dormancy, suggesting its potential use in dormancy-inducing strategies aimed at preventing and/or controlling metastatic disease. Here, we provide an overview of fenretinide’s mechanisms of action in cancer cells, summarize the available clinical evidence and discuss advances achieved with novel formulations. Finally, we discuss the potential integration of fenretinide at different stages of clinical management, with particular emphasis on its prospective use as a chemopreventive strategy or as a therapeutic option for disease control.

Cancers doi: 10.20517/cdr.2026.22

Authors: Yang Liu,Yuxuan Song,Jilin Wu,Jincong Li,Wenbo Yang,Yiqing Du,Caipeng Qin,Tao Xu

Aim: To compare the efficacy and safety of first-line systemic therapies for advanced urothelial carcinoma (UC) and identify the relative benefit–risk profiles of available regimens.

Methods: We conducted a systematic review and Bayesian random-effects network meta-analysis of randomized controlled trials evaluating first-line systemic therapies for advanced UC (INPLASY2025100112). PubMed, Embase, and the Cochrane Library were searched from inception to November 30, 2025. Time-to-event outcomes were summarized as hazard ratios (HRs) with 95% credible intervals (CrIs) for overall survival (OS) and progression-free survival (PFS), and binary outcomes were summarized as odds ratios (ORs) with 95%CrIs for objective response rate (ORR) and grade ≥ 3 adverse events (AEs).

Results: Thirteen trials comparing 10 regimens were included. Immune checkpoint inhibitor plus antibody–drug conjugate (ICI+ADC) was associated with the largest estimated improvements in OS, PFS, and ORR (OS: HR 0.47, 95%CrI 0.37-0.63; PFS: HR 0.45, 95%CrI 0.33-0.63; ORR: OR 2.70, 95%CrI 1.60-4.60) and showed consistent improvements across both cisplatin-eligible and cisplatin-ineligible patients. ICI plus chemotherapy (ICI+Chemo) also improved OS (HR 0.83, 95%CrI 0.70-0.96) and PFS (HR 0.78, 95% CrI 0.63-0.95). ICI monotherapy was associated with the lowest odds of grade ≥ 3 AEs (OR 0.11, 95%CrI 0.03-0.44) but ranked lowest for efficacy.

Conclusion: ICI+ADC may represent a promising first-line option when available. ICI+Chemo remains an appropriate alternative, whereas ICI monotherapy may be reserved for patients unsuitable for combination therapy.

Cancers doi: 10.20517/cdr.2026.10

Authors: Gesine Kretzschmar,Youssif Budagaga,Lisa Groß,Jan-Heiner Küpper,Sarah Kammerer,Jakub Hofman

Aim: Chemotherapeutic resistance is a leading cause of cancer-related mortality worldwide. It has been suggested to be at least partly driven by the activity of uridine diphosphate glucuronosyltransferases (UGTs). However, this hypothesis is primarily supported by indirect evidence with potential confounding factors arising from the use of multienzymatic models among other things. Here we present new HepG2 models transduced with UGT1A1 or UGT2B7 that provide mechanistic insights into the potential role of UGTs in resistance to SN-38, etoposide, and epirubicin.

Methods: The new cellular models were characterised by immunofluorescence, quantitative real-time PCR, and doubling-time assessment. Possible differences in chemotherapeutic efficacy were evaluated using comparative ATP viability assays and an inhibitor-based verification study. Drug combination assays were conducted to determine whether dual-activity modulation could combat enzyme-mediated resistance, using the quantitative Chou-Talalay method to detect synergistic effects. Finally, an advanced physiologically relevant model based on proliferating primary upcyte hepatocytes was characterised and used to verify the results obtained with the transduced models.

Results: The comparative ATP viability assays and verification studies using the UGT inhibitors atazanavir and diclofenac confirmed that both UGT enzymes significantly reduced the tested drugs’ pharmacodynamic activity. Drug combination experiments then showed that UGT1A1 activity can be synergistically targeted by nilotinib and regorafenib via a new dual-activity modulation approach. Finally, the role of UGT1A1 in resistance to SN-38 was confirmed in a complex model based on primary upcyte hepatocytes.

Conclusion: After in vivo confirmation, our findings could potentially be translated into effective and safe combination regimens for oncology patients.

Cancers doi: 10.20517/cdr.2026.02

Authors: Yuxin Zhang,Weiqi Xu,Fangling Cheng,Jinghan Zhu,Yuanxiang Lu,Guangzhen Cai,Jiang Li,Yujie Zhang

Aim: Hepatocellular carcinoma (HCC) remains a formidable worldwide health challenge, characterized by inadequate treatment efficacy and unsatisfactory clinical prognosis. Our previous study implicated LINC01607 in lenvatinib resistance, but its role in HCC progression and ferroptosis-associated vulnerability remains unclear.

Methods: LINC01607 expression was examined in HCC patient samples and The Cancer Genome Atlas datasets. Cellular, animal, and patient-derived organoid (PDO) models were used to evaluate its biological function. RNA sequencing, ferroptosis-related assays, rescue experiments, and drug-sensitivity analyses were performed to explore associated downstream pathways.

Results: LINC01607 was upregulated in HCC tissues and associated with aggressive clinicopathological features and poor survival. Functional assays showed that LINC01607 promoted HCC cell proliferation, migration, invasion, tumor growth, and metastasis. LINC01607 depletion induced ferroptosis-associated changes, including increased lipid peroxidation, glutathione depletion, and Fe²⁺ accumulation under ferroptotic stress, which were partially reversed by ferroptosis inhibitors. LINC01607 knockdown also enhanced sensitivity to RSL3 and sorafenib, while ferrostatin-1 partially rescued the increased sorafenib sensitivity. RNA sequencing and rescue experiments suggested involvement of the p62–Keap1–Nrf2 pathway. LINC01607 depletion was associated with reduced SQSTM1/p62, Nrf2, and ferroptosis-resistance proteins, whereas p62 overexpression partially reversed these effects and Nrf2 knockdown abrogated the rescue. In xenograft and PDO models, LINC01607 depletion improved the response to sorafenib.

Conclusion: LINC01607 contributes to HCC progression and ferroptosis-associated therapy resistance, at least in part through the p62–Keap1–Nrf2 pathway, supporting further investigation of LINC01607 as a potential therapeutic target.

Cancers doi: 10.20517/cdr.2026.33

Authors: Veronica Gatti,Matti van Welzen,Alessandro Napoli,Marc Dubourdeau,Marta Tiberi,Andrea Marra,Giorgia Giorgi,Clémence Gély,Veronica Ceci,Olaf Wolkenhauer,Tommaso Mazza,Shailendra Gupta,Mario Cioce,Valerio Chiurchiù,Vito Michele Fazio

Aim: Malignant pleural mesothelioma (MPM) is a paradigmatic inflammation-associated cancer and a major therapeutic challenge due to its resistance to treatment. Inflammation is thought to promote both tumor progression and therapy resistance. Senescence-associated secretory phenotype (SASP)-mediated, chemotherapy-induced release of arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) contributes to pemetrexed resistance in MPM cells in vitro.

Methods: Pro-inflammatory mediators (PIMs) and specialized pro-resolving mediators (SPMs) were quantified in pleural exudates using liquid chromatography-tandem mass spectrometry. Single-cell RNA-sequencing datasets were analyzed to assess the distribution of SPM-producing enzymes between mesothelial and mesothelioma cells in both tumor tissue and uninvolved pleura. Least Absolute Shrinkage and Selection Operator regression (LASSO) was used to derive a composite prognostic score (CPS) from SPM-related gene expression.

Results: Chemotherapy-treated patients exhibited a reduction in SPMs - including resolvins, protectins, and maresins - alongside increased prostaglandin levels. Single-cell analysis revealed differential partitioning of SPM-producing enzymes, with lower expression in mesothelioma cells compared with mesothelial cells. A five-gene CPS derived from this lipid mediator landscape independently predicted overall survival beyond conventional clinical parameters.

Conclusion: Chemotherapy alters the lipid mediator composition of pleural exudates in MPM by reducing SPMs, thereby disrupting resolution pathways. This effect is consistent with an intrinsic imbalance in expression between mesothelial and mesothelioma cells. Together, these findings suggest that impaired resolution of inflammation contributes to a pro-tumorigenic, pro-inflammatory, and chemoresistant microenvironment in MPM, with potential prognostic implications.

Cancers doi: 10.20517/cdr.2026.37

Authors: Xiaonan Shen,Hao Zhong,Wenqing Jia,Zichao Guo,Haiqin Song,Zhenghao Cai,Xi Cheng,Jianwen Li,Bo Feng,Haoran Feng,Fei Yue

Aim: Colorectal cancer (CRC) ranks among the most prevalent malignancies across the globe, with treatment resistance often closely linked to the complexity of the tumor microenvironment (TME). This study aims to establish a gene signature associated with epithelial-mesenchymal transition (EMT) that integrates TME dynamics, prognosis prediction, and drug resistance assessment in CRC.

Methods: We employed the Cancer Genome Atlas (TCGA) resource and bulk RNA-sequencing profiles linked to EMT to identify common differentially expressed genes (DEGs). An eight-gene signature was constructed using multivariable Cox regression analysis. The correlations of risk groups (scores) with overall survival, biological characteristics, and drug sensitivity were analyzed in CRC patients.

Results: Patients in the high-risk group exhibited significantly worse clinical outcomes than those in the low-risk group. Moreover, a lower risk score was significantly correlated with increased responsiveness to both immune checkpoint inhibitors and 5-fluorouracil in CRC patients. Additionally, experiments in vitro and in vivo confirmed that FABP4 functions as an oncogene in CRC by facilitating cell growth, migration, and chemotherapy resistance.

Conclusion: The EMT-associated gene signature holds significant value for predicting clinical prognosis, immunotherapy responsiveness, and chemotherapy sensitivity in CRC.

Cancers doi: 10.20517/cdr.2026.35

Authors: Zhiliang Li,Wenqing Jia,Zichao Guo,Fang Zheng,Chenhao Huang,Tao Zhang,Zhuoqing Xu,Haoran Feng,Xi Cheng,Ren Zhao

Therapeutic resistance represents a formidable bottleneck in colorectal cancer (CRC) management, severely limiting the clinical efficacy of both conventional regimens and novel immunotherapies. Emerging evidence underscores tertiary lymphoid structure (TLS) - ectopic lymphoid aggregates newly sculpted within the tumor microenvironment (TME) - as pivotal orchestrators of localized antitumor immunity and prime therapeutic targets to circumvent resistance. Distinct from secondary lymphoid organs, TLS facilitate in situ immune cell priming, clonal expansion, and functional differentiation, thereby sustaining a robust adaptive immune response. This review systematically dissects the cellular architecture, maturation dynamics, and spatial heterogeneity of TLS in primary and metastatic CRC, clarifying how these attributes dictate clinical outcomes and treatment responsiveness. Mechanistically, we delineate the molecular networks driving TLS neogenesis, encompassing chemokine cascades, tumor necrosis factor (TNF) superfamily signaling, and interactive crosstalk with the gut microbiota. Furthermore, we summarize cutting-edge preclinical strategies - including stimulator of interferon genes agonists, bio-nanovaccines, and hypofractionated radiotherapy combinations - engineered to trigger TLS neogenesis, promote germinal center (GC) maturation, and enrich stem-like effector tumor-infiltrating lymphocytes (TILs) to convert immunologically “cold” tumors into “hot” niches. By integrating mechanistic paradigms with clinical applications, this review provides a definitive framework for leveraging TLS targeting as a transformative modality to modulate drug resistance and optimize therapeutic trajectories in CRC; the graphical abstract is shown below.

Cancers doi: 10.20517/cdr.2026.42

Authors: Eleicy Nathaly Mendoza,Serena Castelli,Angela De Cristofaro,Enrico Desideri,Grazia Graziani,Pedro Miguel Lacal,Maria Rosa Ciriolo,Fabio Ciccarone

Aim: This study investigates the role of Ten-Eleven Translocation (TET) dioxygenases in melanoma-acquired resistance to BRAF inhibitors (BRAFi), focusing on their contributions to epigenetic remodeling and redox balance.

Methods: Dabrafenib-resistant A375 and M14 melanoma cell lines were generated and analyzed for TET family expression. Transcriptomic data from independent RNA-seq datasets of BRAFi-resistant melanoma models were used for validation. Cells were treated with high-dose L-ascorbic acid (ASC), a cofactor enhancing TET activity, and assessed for 5-hydroxymethylcytosine (5hmC) levels, reactive oxygen species (ROS) production, and cytotoxicity. Antioxidant capacity and expression of GLUT1, a transporter for oxidized ASC, were evaluated. TET2 was silenced to determine its functional role in ASC-mediated effects.

Results: BRAFi-resistant cells displayed reduced TET2 expression and altered levels of other TET family members, consistent with RNA-seq data. ASC treatment increased 5hmC levels and induced ROS-dependent cytotoxicity predominantly in parental cells, while resistant cells were less sensitive. Resistant cells exhibited enhanced antioxidant defenses and reduced GLUT1 expression. TET2 silencing diminished ASC-induced 5hmC accumulation, ROS production, and GLUT1 expression, indicating a central role for TET2 in mediating ASC cytotoxicity.

Conclusion: These findings identify a TET2-dependent epigenetic–metabolic axis that regulates redox vulnerability in melanoma. The link between TET2 activity, GLUT1 expression, and ROS-mediated cytotoxicity highlights potential biomarkers and therapeutic targets to overcome resistance to BRAFi.

Cancers doi: 10.20517/cdr.2026.39

Authors: Feiyi Xu,Can Zhang,Sihan Wu,Yang Li,Yonggang Chen,Youwei Zhang

Aim: Cisplatin (DDP) represents the first-line chemotherapeutic agent for lung adenocarcinoma (LUAD), but acquired resistance severely limits its efficacy. This study investigated the role of the mitochondria-associated long non-coding RNA (mt-lncRNA) LINC01133 and its mechanisms in cisplatin resistance in LUAD.

Methods: LINC01133 expression and subcellular localization were detected through high-throughput mitochondrial RNA sequencing, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and fluorescence in situ hybridization (FISH). By modulating LINC01133 expression, we evaluated its effect on cisplatin resistance and malignant phenotypes. Further, western blotting, enzyme-linked immunosorbent assays (ELISAs), and calcium fluorescent probes were used to analyze how LINC01133 affects the Caspase-1/GSDMD signaling pathway, mitochondrial calcium homeostasis, and mitochondrial function. Finally, in vitro rescue experiments and a xenograft mouse model were conducted to validate the function of LINC01133 and its key targets.

Results: LINC01133 expression markedly increased in A549/DDP cells and was enriched in mitochondria. Clinical analysis revealed a difference in LINC01133 expression between LUAD and normal lung tissues, and higher LINC01133 expression was associated with poor patient survival. Functionally, LINC01133 overexpression enhanced cisplatin resistance and malignant phenotypes in A549 cells, whereas its knockdown reversed the resistance phenotype and inhibited malignant behaviors in A549/DDP cells. Mechanistically, cisplatin triggered the Caspase-1/GSDMD pathway to induce pyroptosis. LINC01133 inhibited activation of this pathway, alleviating GSDMD-NT-mediated mitochondrial calcium overload and thereby preserving mitochondrial structural integrity and function, ultimately enhancing cisplatin resistance.

Conclusion: LINC01133, a mitochondria-enriched oncogenic lncRNA, promotes cisplatin resistance in LUAD by inhibiting the Caspase-1/GSDMD pathway and maintaining mitochondrial calcium homeostasis and function.

Cancers doi: 10.20517/cdr.2026.58

Authors: Tung-Wei Hsu,Chih-Ming Su,Yen-Hao Su,Po-Hsiang Liao,Charupong Saengboonmee,Wan-Yu Wang,Hsin-An Chen

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal human malignancies and is characterized by profound metabolic reprogramming and marked therapeutic resistance. Among the metabolic enzymes that sustain tumor fitness, adenylosuccinate lyase (ADSL) has emerged as a critical regulator of de novo purine biosynthesis with broader roles in oncogenic signaling, metabolic adaptation, and chemoresistance. ADSL catalyzes two key reactions in purine synthesis, contributing to adenylosuccinate-to-adenosine monophosphate (AMP) production, fumarate generation, and regulation of intermediates such as succinylaminoimidazole carboxamide ribotide (SAICAR), which functionally intersects with glycolysis and transcriptional control. In PDAC, dysregulation of ADSL-associated metabolism has been linked to aggressive tumor biology and altered therapeutic responses. Mechanistically, ADSL may modulate gemcitabine responsiveness through context-dependent effects on purine nucleotide homeostasis, replication-stress adaptation, redox regulation, and ferroptosis-associated signaling. Beyond its canonical biosynthetic function, ADSL-related metabolic flux may support adaptive survival through SAICAR–pyruvate kinase M2 (PKM2) signaling, glycolytic remodeling, and fumarate-associated pathways that influence redox homeostasis, epigenetic regulation, and stress-response signaling. These interconnected mechanisms position ADSL as a context-dependent metabolic vulnerability in chemoresistant PDAC. Here, we summarize current understanding of ADSL biology and discuss its prognostic, mechanistic, and therapeutic relevance in PDAC chemoresistance, with emphasis on gemcitabine resistance, replication stress buffering, and metabolic adaptation. Targeting ADSL-associated metabolic dependencies may provide a promising strategy to disrupt the metabolic circuitry underlying PDAC aggressiveness and drug resistance.

Cancers doi: 10.20517/cdr.2026.57

Authors: Melis Poyraz,Buse Sari,Jérôme Ambroise,Melanie Spears,Martin Michaelis, Jindrich Cinatl Jr.,Romain Boidot,Kristian Serafimov,Olivier Feron,François P. Duhoux,Manon Desgres,Cyril Corbet

Aim: Resistance to neoadjuvant chemotherapy remains a major challenge in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer (BC). Although anthracyclines and taxanes constitute the standard sequential regimen, the metabolic adaptations accompanying resistance to these agents remain poorly defined. We investigated whether chemoresistance is associated with shared or drug-specific metabolic alterations.

Methods: Parental MCF-7 and ZR-75-1 cells and their anthracycline-, and taxane-resistant derivatives, were characterized through multi-omics, Seahorse-based metabolic flux, and pharmacological inhibition analyses, alongside validation in patient transcriptomic datasets.

Results: Chemoresistant cells displayed reduced drug sensitivity and improved recovery following treatment withdrawal. Transcriptomic profiling revealed extensive yet largely distinct gene expression changes among resistant models, whereas metabolomics showed limited divergence. Functional studies demonstrated concurrent reductions in mitochondrial respiration and glycolytic capacity, indicating a low-bioenergetic phenotype without compensatory metabolic rewiring. Lipidomic changes were heterogeneous and model-dependent. Despite this overall metabolic constraint, spermidine and spermine levels were increased across all resistant models, whereas upregulation of the polyamine-related genes ATP13A4 and SAT1 was specific to anthracycline-resistant cells. Chemoresistant phenotypes conferred reduced sensitivity to mitochondrial inhibitors. In contrast, sensitivity to polyamine pathway inhibition varied across models. Clinical datasets corroborated key experimental features, showing increased ATP binding cassette subfamily B member 1 (ABCB1) expression and significant post-treatment suppression of oxidative phosphorylation and glycolysis signatures. Polyamine pathway enrichment trends were less uniform, reflecting clinical heterogeneity.

Conclusion: Chemoresistance in HR+/HER2- BC is characterized by heterogeneous transcriptional remodeling but relative metabolic constraint. Clinical dataset validation confirms post-chemotherapy bioenergetic suppression, while polyamine alterations represent context-dependent adaptations rather than universal vulnerabilities.

Cancers doi: 10.20517/cdr.2026.66

Authors: Yuxi Yang,Binghui Liang,Weijie Hong,Sau Har Lee,Dongfang Tang,Shuxian Xie,Changtai Qin,Liu Shen,Zhumei Sun,Xiaofeng Yan,Hua Li,Xiaoling Wang,Xudong Hu,Tingjie Ye,Wei Zhang,Wei Xu

Aim: Despite the contribution of cancer stem-like cells (CSLCs) to acquired paclitaxel resistance in non-small cell lung cancer (NSCLC), the biomarkers and regulatory mechanisms sustaining their stemness under chemotherapy pressure remain poorly understood. This study aimed to identify the stemness-maintaining programs underlying CSLC-associated paclitaxel resistance.

Methods: Paclitaxel-resistant NSCLC cell models were established. RNA-seq data from resistant spheres and adherent resistant cells were integrated with Gene Ontology/Kyoto Encyclopedia of Genes and Genomes/gene set enrichment analysis and patient transcriptomic datasets to identify CSLC maintenance-associated candidate biomarkers. Inhibitors, sphere-forming assays, CD104^-CD166⁺CD49f^hi flow cytometry, reverse transcription quantitative polymerase chain reaction, western blotting, and ST6GAL1 knockdown or overexpression were used for functional and mechanistic validation. Sambucus nigra agglutinin lectin blotting was performed to assess epidermal growth factor receptor (EGFR) α2,6-sialylation. Clinical relevance was assessed using ST6GAL1 immunohistochemistry on 46 clinical lung tumor tissues.

Results: Paclitaxel-resistant NSCLC cells exhibited enhanced sphere formation and CD104^-CD166⁺CD49f^hi expansion. N-glycosylation was activated in resistant spheres. A seven-gene N-glycosylation signature was identified as a CSLC-associated candidate biomarker in acquired paclitaxel resistance. Inhibiting N-glycosylation suppressed the EGFR-mTOR-SOX2/BMI1 axis, decreased CSLCs, and restored paclitaxel sensitivity. ST6GAL1 regulated EGFR α2,6-sialylation. ST6GAL1 depletion also decreased EGFR abundance, suppressed mTOR-SOX2/BMI1 signaling, and sensitized paclitaxel-resistant spheres to paclitaxel rather than adherent cells. ST6GAL1 expression, which was higher in tumors from patients who underwent chemotherapy, showed a trend toward poorer survival among chemotherapy-treated patients. The seven-gene signature was associated with shorter disease-free survival but not overall survival in lung cancer patients.

Conclusions: ST6GAL1-mediated α2,6-sialylation of EGFR contributes to the maintenance of CSLC-associated paclitaxel resistance through mTOR-SOX2/BMI1 signaling. These findings identify ST6GAL1-dependent EGFR sialylation as a potential therapeutic target in CSLC-associated chemoresistance.

Cancers doi: 10.20517/cdr.2026.52

Authors: Marco Pagano Mariano,Enrica Sgarilli,Dirk Mijnlieff,Bonifiya Visuvasam,Andrea Blesio,Graziana Digiacomo,Andrea Cavazzoni,Manuela Ferracin,Elisa Giovannetti

Oncogenic KRAS mutations are a defining feature of pancreatic ductal adenocarcinoma (PDAC), one of the most lethal solid malignancies, characterized by poor responsiveness to chemotherapy. Recent clinical successes of direct KRAS inhibitors in other cancer types have renewed interest in KRAS-directed therapy for PDAC. However, early clinical experience has revealed often short-lived responses, highlighting the rapid emergence of resistance and the need to understand the mechanisms limiting durable benefit. This review summarizes current knowledge on molecular resistance to RAS-directed inhibitors in PDAC, organized into five categories: intrinsic resistance, KRAS-dependent mechanisms, KRAS-independent bypass signaling, downstream pathway reactivation, and tumor microenvironment (TME)-mediated resistance. Evidence from PDAC models is integrated with insights from other KRAS-driven malignancies, particularly non-small cell lung cancer, where direct KRAS inhibition has been studied extensively. Collectively, resistance appears to arise from layered adaptive processes rather than single alterations, including secondary KRAS mutations, receptor tyrosine kinase-driven bypass signaling, reactivation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways, stromal-mediated protection, and reduced drug exposure. Notably, until recently, most evidence in PDAC has been indirect, while direct investigation of resistance mechanisms in KRAS-targeted settings has expanded rapidly only in recent years. Building on these advances, ongoing clinical trials increasingly explore rational combination strategies targeting upstream regulators, downstream effectors, and the TME. However, critical challenges persist, including patient selection, treatment sequencing, toxicity, and the lack of pharmacodynamic frameworks. Overcoming resistance will require mechanistically guided combinations, improved disease-specific models, and biomarker-driven adaptive strategies to ultimately achieve durable clinical benefits in PDAC.

Cancers doi: 10.20517/cdr.2026.79

Authors: Wolfram C. M. Dempke,Klaus Fenchel,Loretta Sullivan,Martin Reck

Tyrosine kinase inhibitors (TKIs) have significantly changed the treatment of non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations, and osimertinib is now established as first-line therapy for NSCLCs. Combination therapies (e.g., osimertininb plus chemotherapy; lazertinib plus amivantamab) have been shown to improve median progression-free survival (mPFS) and median overall survival (mOS) relative to monotherapy. However, due to several resistance mechanisms, patients experience disease progression following EGFR TKI treatment. On-target resistance mechanisms include additional mutations (e.g., C797S/G/N, L718Q, L844V, G724X). Within the heterogeneous group of off-target resistance mechanisms, human epidermal growth factor receptor 2 (HER2) amplifications, mesenchymal-epithelial transition factor (MET) alterations, oncogenic fusions (e.g., BRAF, FGFR, RET), histological changes, epithelial-mesenchymal transitions, and alterations of the RAS/MEK/ERK and the PI3K/AKT/mTOR signal transduction pathways are critical and can confer resistance to EGFR TKIs. Several drugs have been identified to inhibit these pathways, with some of them already approved for clinical use. Most fourth-generation EGFR TKIs are orally bioavailable and are mainly allosteric thiazole amide-based reversible inhibitors. Their activity results from selective binding to an allosteric site, which can alter the EGFR protein conformation, allowing them to bypass C797X. A recommendation for the optimal treatment strategy and sequence for NSCLC patients with acquired EGFR TKI-resistant tumours still cannot be given. An improved understanding of the underlying resistance mechanisms will help to pave the way for the development of innovative and highly specific drugs for the therapy of osimertinib-resistant NSCLCs. The putative clinical relevance of fourth-generation EGFR TKIs for NSCLC patients needs to be defined, and many development hurdles need to be cleared before victory can be declared.

Cancers doi: 10.20517/cdr.2025.200

Authors: Haojie Yang,Yingzhe Yan,Zicong Tan,Xiaoying Xu,Kang Chen,Qin Li,Ning Liufu,Fengtao Ji

Aim: Cisplatin resistance remains a major obstacle to the effective treatment of tongue squamous cell carcinoma (TSCC). This study is dedicated to elucidating the role and mechanism of circular RNA (circRNA) hsa-circ-0001030 in modulating cisplatin sensitivity and metabolic reprogramming in TSCC.

Methods: CircRNA sequencing, quantitative polymerase chain reaction, and RNA fluorescence in situ hybridization were used to test hsa-circ-0001030 expression in TSCC tissues and cell lines. Gain-of-function assays (colony formation, cell counting kit-8, Transwell assay, and xenograft models) were conducted to evaluate proliferation, invasion, and cisplatin response. Mechanistic studies, including RNA pull-down, RNA-binding protein immunoprecipitation, and western blotting, were performed to identify pyruvate kinase M2 (PKM2) as a binding partner of hsa-circ-0001030 and to assess glycolytic activity, glucose uptake, and lactate production.

Results: Hsa-circ-0001030 was markedly downregulated in TSCC and cisplatin-resistant cells. Overexpression of hsa-circ-0001030 suppressed tumor growth, migration, and glycolytic flux, while enhancing cisplatin sensitivity both in vitro and in vivo. Mechanistically, hsa-circ-0001030 directly bound to PKM2 at nucleotides 138-169, inhibited PKM2 enzymatic activity, restraining tetramer formation and increased tyrosine 105 (Tyr105) phosphorylation and thereby blocking PKM2-driven glycolysis. Clinically, low hsa-circ-0001030 expression correlated with advanced tumor-node-metastasis stage, poor differentiation, and unsatisfying prognosis in TSCC patients.

Conclusion: Hsa-circ-0001030 acted as a tumor-suppressive circRNA that might depress PKM2-dependent metabolic reprogramming and cisplatin resistance in TSCC, highlighting its potential as a prognostic biomarker and therapeutic target for overcoming chemoresistance.