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.

Aim: Cyclin-dependent kinases 4 and 6 (CDK4/6) are frequently upregulated in pancreatic ductal adenocarcinoma (PDAC) and are associated with poor overall survival. Although CDK4/6 inhibition suppresses tumor cell proliferation, it paradoxically promotes metastasis and invasion, and the mechanisms underlying this effect remain unclear.Methods: We evaluated the effects of the CDK4/6 inhibitor palbociclib (PD-0332991) and the bromodomain and extra-terminal (BET) inhibitor JQ1, administered individually and in combination, on human PDAC cell lines in vitro and on tumor growth in an orthotopic mouse model.Results: Palbociclib modestly inhibited pancreatic tumor growth but significantly enhanced tumor cell migration, invasion, and epithelial-to-mesenchymal transition (EMT). In contrast, co-treatment with JQ1 potentiated palbociclib’s anti-proliferative effects and reversed EMT. Mechanistically, CDK4/6 inhibition activated the canonical Wnt/β-catenin pathway via Ser9 phosphorylation of GSK3β, whereas BET inhibition disrupted the cross-talk between Wnt/β-catenin and TGF-β/Smad signaling. Combined inhibition of CDK4/6 and BET produced a synergistic antitumor effect in vitro and in vivo.Conclusion: Our findings support a combined therapeutic strategy targeting CDK4/6 and BET proteins to achieve synergistic inhibition of PDAC progression.

Aim: Urinary bladder cancer (UBC) often develops chemoresistance, reducing treatment effectiveness. This study aimed to investigate diverse molecular mechanisms underlying acquired resistance by establishing and characterizing a comprehensive panel of UBC cell lines resistant to common chemotherapeutics.Methods: Fifteen UBC cell lines were examined: three parental lines (RT-112, TCC-SUP, UMUC-3) and twelve derived sublines adapted to cisplatin, vinblastine, or gemcitabine. Drug sensitivity was assessed using the SRB assay. Resistance mechanisms were explored via quantitative real-time PCR (targeting genes including ABCB1, dCK, hENT1, ECHDC1, TUBB3), Western blotting (assessing proteins such as p21, Cyclin B, and Mcl-1), and biochemical assessment of glutathione levels and redox state.Results: The adapted sublines exhibited distinct resistance profiles and cross-resistance patterns. Gene expression and protein analyses revealed drug- and lineage-specific alterations, involving factors such as p21, Cyclin B, and Mcl-1. Changes in glutathione metabolism were also associated with resistance. Notably, no single, universal mechanism accounted for resistance across the entire panel.Conclusion: UBC cells develop diverse, context-dependent adaptive strategies to resist cisplatin, vinblastine, and gemcitabine. These findings highlight the complexity of chemoresistance mechanisms. The characterized cell line panel represents a valuable resource for future studies aimed at understanding and overcoming drug resistance in bladder cancer, suggesting that personalized therapeutic approaches may be necessary.

Aim: Muscle-invasive bladder cancer (MIBC) remains lethal despite promising oncolytic virotherapy, hindered by tumor-intrinsic resistance. This study aimed to elucidate the molecular basis underlying differential sensitivity to the oncolytic M1 virus in bladder cancer.Methods: Bladder cancer cell lines with varying sensitivity to M1 were analyzed for endoplasmic reticulum (ER) stress responses and unfolded protein response (UPR) pathway activation. IRE1α expression was modulated using small interfering RNA and a selective inhibitor. Viral cytotoxicity, replication, and apoptosis were assessed using viability assays, immunofluorescence, electron microscopy, and immunoblotting. In vivo antitumor efficacy was assessed using xenografted mice. Clinical relevance was examined using patient-derived cells and survival data from The Cancer Genome Atlas.Results: M1 virus induced ER stress and apoptosis in sensitive cells (e.g., T24, UM-UC-3) supporting viral protein expression, whereas low-sensitivity cells like EJ showed minimal response due to limited viral replication. In moderately sensitive cells, M1 replication led to viral protein accumulation, triggering IRE1α upregulation, which in turn limited further protein buildup and apoptosis. IRE1α inhibition enhanced M1-induced ER stress, apoptotic signaling, and oncolysis without affecting viral replication capacity. In vivo, M1 plus STF083010 achieved greater tumor suppression than monotherapy without added toxicity. Analysis of patient-derived cells and TCGA data further revealed downregulation of IRE1α in primary tumors and its potential association with worse prognosis.Conclusion: IRE1α modulates M1-induced viral protein accumulation and cell death. Inhibiting IRE1α enhances ER stress and potentiates the oncolytic effect of M1 virus. Targeting IRE1α may improve M1-based virotherapy outcomes in accessible tumors.

Aim: The immune evasion mechanisms of gastric cancer are complex, involving various cellular dysfunctions within the tumor microenvironment. Recently, there has been growing interest in how cancer-associated fibroblasts (CAFs) contribute to tumor immune evasion. However, the precise molecular pathways through which CAFs drive immune escape in the context of gastric cancer are not yet fully elucidated.Methods: The abundance of FAP+CAFs in gastric cancer tissues was assessed by immunohistochemistry (IHC), and its correlation with tumor sensitivity to PD-1 monoclonal antibody therapy was analyzed. To study the effect of FAP+CAFs on naive CD4+ T cell differentiation, co-culture experiments were conducted. The underlying molecular mechanisms were further investigated through western blotting and in vivo animal experiments.Results: FAP+CAFs were significantly increased in gastric cancer tissues resistant to PD-1 monoclonal antibody, and a positive correlation was found with Th2 cells. Additionally, the expression and secretion of IL-31 in FAP+CAFs cells were elevated. Mechanistically, IL-31 interacts with the IL-31R expressed on naive CD4+ T cells, leading to the activation of the STAT6 signaling pathway. This cascade facilitates the differentiation of naive CD4+ T cells into Th2 cells, thereby contributing to resistance against anti-PD-1 therapy in gastric cancer.Conclusion: FAP+CAFs may reduce sensitivity to anti-PD-1 therapy in gastric cancer by promoting Th2 polarization of naive CD4+ T cells via the IL-31/STAT6 signaling pathway. Targeting this axis could offer a potential strategy to improve immunotherapy outcomes, although further validation is required.

Breast cancer continues to be the primary cause of cancer-related deaths among women globally, with increased rates of incidence and mortality, highlighting the critical need for effective treatment strategies. Recent developments have introduced a variety of treatment options that address the molecular diversity of breast cancer; nonetheless, drug resistance remains a significant barrier to achieving favorable results. This review explains the crucial role of genetic and epigenetic changes in contributing to therapeutic resistance, in addition to other factors such as increased drug efflux, enhanced DNA repair, evasion of senescence, tumor heterogeneity, the tumor microenvironment (TME), and epithelial-to-mesenchymal transition (EMT). Genetic modifications, including mutations in oncogenes and tumor suppressor genes, disrupt essential signaling pathways, facilitating resistance to chemotherapy and targeted therapies. At the same time, epigenetic modifications - like DNA methylation, alterations to histones, and dysregulation of non-coding RNAs - reprogram gene expression, supporting adaptive resistance mechanisms. These molecular abnormalities contribute to the plasticity of tumors, allowing cancer cells to evade therapeutic approaches. This review consolidates recent discoveries regarding how these genetic and epigenetic modifications affect treatment responses and resistance in breast cancer, highlighting their interaction with disease advancement. By pinpointing new drug targets, including immunotherapeutic strategies, this article seeks to shed light on the molecular underpinnings of chemoresistance, aiding in the refinement of existing treatment protocols. A more profound understanding of these mechanisms offers the potential for developing precision therapies to overcome resistance, reduce relapse rates, and improve clinical outcomes for breast cancer patients.

Aim: Acquired resistance to 5-fluorouracil/leucovorin (5-FU/LV) frequently develops during treatment of metastatic colorectal (mCRC), but the causes are incompletely understood. We aim to: (i) identify the causes of 5-FU/LV resistance under physiological folate; and (ii) determine if a polymeric fluoropyrimidine (FP) CF10 remains potent to CRC cells selected for 5-FU/LV resistance.Methods: 5-FU/LV-resistant CRC cells were selected by repeated passaging with increasing 5-FU/LV concentrations, and resistance factors were calculated from dose-response studies. Basal and treatment-induced thymidylate synthase (TS), Myc, and ABCB5 were determined by RT-qPCR and Western blot. TS activity was determined using an in situ3H-release assay. DNA topoisomerase 1 cleavage complexes (Top1cc) and DNA double-strand breaks (DSBs) were determined by immunofluorescence.Results: Acquired resistance to 5-FU/LV with physiological folate was associated with a <1.5-fold increase in basal TS levels; however, with either 5-FU/LV or CF10/LV treatment, TS levels were elevated ~5-fold by Western blot but only ~2-fold by RT-qPCR. CF10 remained very potent to CRC cells selected for 5-FU/LV resistance, and CF10 effectively induced TS ternary complex formation and inhibited TS catalytic activity in 5-FU/LV-resistant CRC cells. c-Myc was expressed at ~4-fold higher levels in 5-FU/LV-resistant CRC cells, but Myc was barely detectable with CF10/LV treatment. The Myc-target ABCB5, which is an established factor in resistance to 5-FU and other drugs, was substantially downregulated with CF10/LV but not 5-FU/LV treatment.Conclusion: Acquired 5-FU/LV resistance was associated with FP-induced TS and elevated Myc and ABCB5. There is minimal cross-resistance to CF10 in 5-FU/LV-resistant CRC cells, consistent with its use in treating 5-FU/LV-resistant mCRC.

Tumor organoids were modeled in vitro to mimic in vivo culture conditions, allowing tumor-derived tissue cells or isolated and purified tumor stem cells to self-assemble into 3D preclinical models that are similar to tissues and organs in vivo. Compared with traditional models, tumor organoids not only resemble parental tumors in histology and genomics, capturing their heterogeneity and drug response, but also provide an efficient platform for long-term culture, maintaining genetic stability and enabling gene manipulation. Therefore, tumor organoids have unique advantages in cancer drug resistance research. The paper covers: (1) Modeling methods of epithelial and non-epithelial tumor organoids, with special emphasis on the modeling of drug-resistant organoids; (2) Their use in drug resistance research, split into i. Therapeutic exploration (drug testing and screening) and ii. Mechanism investigation (use drug-resistant organoids to study drug resistance), including methods and findings from various teams.

The induction of cell death is recognized as a potent strategy for cancer treatment. Apoptosis is an extensively studied form of cell death, and multiple anticancer drugs exert their therapeutic effects by inducing it. Nonetheless, apoptosis evasion is a hallmark of cancer, rendering cancer cells resistant to chemotherapy drugs. Consequently, there is a growing interest in exploring novel non-apoptotic forms of cell death, such as ferroptosis, necroptosis, pyroptosis, and paraptosis. Natural compounds with anticancer properties have garnered significant attention due to their advantages, including a reduced risk of drug resistance. Over the past two decades, numerous natural compounds have been discovered to exert anticancer and anti-resistance effects by triggering these four non-apoptotic cell death mechanisms. This review primarily focuses on these four non-apoptotic cell death mechanisms and their recent advancements in overcoming drug resistance in cancer treatment. Meanwhile, it highlights the role of natural compounds in effectively addressing cancer drug resistance through the induction of these forms of non-apoptotic cell death.

Aim: Neo-adjuvant chemotherapy is a common approach for the complex treatment of breast cancer (BC) and paclitaxel (PTX) is frequently included in the therapeutic regimen. However, the effect of PTX-based treatment is hard to predict precisely based on routinely used markers. As microRNAs are considered a new promising class of biomarkers, the link between miRNA expression and PTX resistance of BC cells needs to be well investigated. This study aimed at the identification of miRNAs associated with responses of BC cells to PTX.Methods: Intrinsic PTX sensitivity and miRNA profiling were assayed in five BC cell lines to identify candidate miRNAs. Selected miRNA (n. 15) expressions were analyzed by real-time-quantitative polymerase chain reaction (RT-qPCR) in BC tissue samples (n. 31) obtained from a diagnostic biopsy. Results were analyzed in the context of the effect of two cycles of PTX and the effect of the completed scheme of neoadjuvant therapy. The study’s design facilitated the evaluation of the effect of PTX on cells and the identification of features of the microRNA expression profiles associated exclusively with sensitivity to this drug.Results: miR-186 and miR-7 expression in BC tissues was higher in patients with better outcomes of PTX-based neoadjuvant therapy.Conclusion: High expressions of miR-186 and miR-7 are associated with good response to PTX, whereas their low expressions may be associated with resistance to PTX in BC, indicating the possibility of developing innovative test systems for the prediction of the PTX response, which can be used before the start of neo-adjuvant chemotherapy for BC.