癌症耐药(英文)最新文献

Primary and secondary resistance to immune checkpoint blockade (ICB) reduces its efficacy. The mechanisms underlying immunotherapy resistance are highly complex. In non-small cell lung cancer (NSCLC), these mechanisms are primarily associated with the loss of programmed cell death-ligand 1 (PD-L1) expression, genetic mutations, circular RNA axis and transcription factor regulation, antigen presentation disorders, and dysregulation of signaling pathways. Additionally, alterations in the tumor microenvironment (TME) play a pivotal role in driving immunotherapy resistance. Primary resistance is mainly attributed to TME alterations, including mutations and co-mutations, modulation of T cell infiltration, enrichment of M2 tumor-associated macrophages (M2-TAMs) and mucosal-associated invariant T (MAIT) cells, vascular endothelial growth factor (VEGF), and pulmonary fibrosis. Acquired resistance mainly stems from changes in cellular infiltration patterns leading to "cold" or "hot" tumors, altered interferon (IFN) signaling pathway expression, involvement of extracellular vesicles (EVs), and oxidative stress responses, as well as post-treatment gene mutations and circadian rhythm disruption (CRD). This review presents an overview of various mechanisms underlying resistance to ICB, elucidates the alterations in the TME during primary, adaptive, and acquired resistance, and discusses existing strategies for overcoming ICB resistance.

Aims: Circulating tumour cells (CTCs) can be detected in peripheral blood using their physical properties (increased size and less deformable than normal circulating blood cells) or using cell surface markers. The study of these CTCs should provide important insights into tumour biology, including mechanisms of drug resistance. We performed a pilot study (IRAS ID: 235459) to evaluate if CTCs could be isolated from peripheral blood samples collected from soft tissue sarcoma (STS) patients. Methods: We used a combined approach that first enriched samples for CTCs using a microfluidic cassette via Parosrtix^TMPR1, and then sorted cells stained for vimentin and cytokeratin using the DEPArray^TM. The total circulating cell-free DNA (cfDNA) level was also analysed. Data were correlated with clinical parameters. Results: 13 patients were recruited to this study: 7 patients with localised disease and 6 patients with metastatic disease. CTCs exhibited a high heterogeneity based on their expression of mesenchymal and epithelial markers. There was no significant difference in the number of CTCs between patients with localised versus metastatic disease. We observed no correlation between CTC numbers and cfDNA; however, the number of CTCs did correlate with primary tumour size. Conclusion: The present study demonstrates the presence of CTCs in STS patients with localised and advanced disease. Further and larger studies are needed to characterise STS CTCs and to evaluate their prognostic significance.

Drug resistance is a major challenge in cancer therapy that often leads to treatment failure and disease relapse. Despite advancements in chemotherapeutic agents and targeted therapies, cancers often develop drug resistance, making these treatments ineffective. Extracellular vesicles (EVs) have gained attention for their potential applications in drug delivery because of their natural origin, biocompatibility, and ability to cross biological barriers. Using the unique properties of EVs could enhance drug accumulation at target sites, minimize systemic toxicity, and precisely target specific cells. Here, we discuss the characteristics and functionalization of EVs, the mechanisms of drug resistance, and the applications of engineered EVs to overcome drug resistance. This review provides a comprehensive overview of the advancements in EV-based drug delivery systems and their applications in overcoming cancer drug resistance. We highlight the potential of EV-based drug delivery systems to revolutionize cancer therapy and offer promising strategies for more effective treatment modalities.

With the growing incidence of obesity-related malignancies, glucagon-like peptide-1 (GLP-1) receptor agonists represent an intriguing potential clinical avenue for cancer prevention and treatment. Population-based data suggest that individuals who have taken GLP-1 receptor agonists have a decreased incidence of obesity-related cancers. Moreover, in vivo and in vitro studies have demonstrated the antitumor activity of these agents independent of other antineoplastic therapeutics. Additionally, other pre-clinical studies have shown that GLP-1 receptor agonists may help overcome resistance to chemotherapy-refractory cancer cells, thus demonstrating a plausible role in cancer treatment. Randomized controlled trials utilizing GLP-1 receptor agonists in both cancer prevention and treatment may allow for a better understanding of the role of these agents in modern oncology.

Aim: Resistance to hormonal and targeted therapies in breast cancer limits treatment efficacy. Epigenetic alterations, including changes mediated by DNA methyltransferases, play a key role in this process. Previously, we identified that resistance to tamoxifen and rapamycin is associated with the suppression of DNMT3A. This study aims to further explore the mechanisms underlying this suppression, with a focus on identifying NR6A1 as a novel regulatory factor. Methods: Acquisition of resistant breast cancer cell sublines, MTT-test, immunoblotting, transient transfection and reporter analysis, lentiviral infection, qRT-PCR, and analysis of methylation using bisulfite pyrosequencing. Results: Our findings indicate that the development of cross-resistance in breast cancer cells to hormonal and targeted therapies involves a shift in cell signaling to alternative AKT pathways, marked by a localized suppression of the NR6A1/DNMT3A axis and associated DNA methylation changes. We demonstrated the critical role of NR6A1 downregulation in resistance development. Additionally, we observed activation of Snail - a key regulator in the epithelial-mesenchymal transition - as a mediator of the effects of NR6A1 depletion, establishing a direct link between Snail expression and resistance formation. Conclusion: The coordinated suppression of NR6A1 and DNMT3A may contribute to sustaining the resistant phenotype in breast cancer cells. This pathway could serve as a predictive marker, helping guide the selection of optimal therapeutic strategies for breast cancer treatment in the future.

Ferroptosis is an iron-dependent cell death characterized by increased intracellular lipid peroxidation. Inducing ferroptosis has shown significant potential in eliminating various malignancies. However, the effectiveness of ferroptosis-based treatments is hampered by the intrinsic or acquired resistance of some tumors. In this review, we delineate the known mechanisms that regulate ferroptosis sensitivity and summarize the therapeutic application of ferroptosis inducers in cancer. Additionally, we discuss the roles of diverse signaling pathways that contribute to ferroptosis resistance in cancer cells, including the glutathione (GSH) and coenzyme Q (CoQ) pathways, NFE2-like bZIP transcription factor 2 (NRF2) antioxidant response, and lipid and iron metabolism. This emerging knowledge may serve as a foundation for developing novel anticancer strategies to overcome ferroptosis resistance.

The emergence of drug resistance leading to cancer recurrence is one of the challenges in the treatment of cancer patients. Several mechanisms can lead to drug resistance, including epigenetic changes. Histone deacetylases (HDACs) play a key role in chromatin regulation through epigenetic mechanisms and are also involved in drug resistance. The control of histone acetylation and the accessibility of regulatory DNA sequences such as promoters, enhancers, and super-enhancers are known mechanisms by which HDACs influence gene expression. Other targets of HDACs that are not histones can also contribute to resistance. This review describes the contribution of HDACs to the mechanisms that, in some cases, may determine resistance to chemotherapy or other cancer treatments.

Resistance of cancer to therapy is the main challenge to its therapeutic management and is still an unsolved problem. Rearranged lipid metabolism is a strategy adopted by cancer cells to counteract adversity during their evolution toward aggressiveness and immune evasion. This relies on several mechanisms, ranging from altered metabolic pathways within cancer cells to evolved dynamic crosstalk between cancer cells and the tumor microenvironment (TME), with some cell populations at the forefront of metabolic reprogramming, thereby contributing to the resistance of the whole ecosystem during therapy. Unraveling these mechanisms may contribute to the development of more effective combinatorial therapy in resistant patients. This review highlights the alterations in lipid metabolism that contribute to cancer progression, with a focus on the potential clinical relevance of such findings for the management of therapy resistance.

Aim: Gastric cancer (GC) is one of the common malignant tumors, and most patients with advanced GC often develop chemotherapy resistance, resulting in poor chemotherapy efficacy. Therefore, it is crucial to clarify the specific mechanisms of their chemotherapy resistance. Methods: In this study, we analyzed the correlation between fos-related antigen-1 (Fra-1) and chemotherapy resistance in GC using bioinformatics, cell counting kit-8 (CCK8), and 5-ethynyl-2'-deoxyuridine (EDU) combined with flow cytometry; furthermore, we used energy metabolomics sequencing, combined with ChIP-qPCR technology, to elucidate the specific role of Fra-1 in chemotherapy resistance of GC cells and its related mechanisms. Results: We found that high Fra-1 expression was closely related to chemotherapeutic drugs in GC cells, as demonstrated by bioinformatics analysis combined with EDU and CCK8 experiments. Energy metabolomics combined with in vitro cellular experimental analysis revealed that the pentose phosphate pathway (PPP) was activated in GC cells with high Fra-1 expression, along with an increase in the synthesis of metabolites such as nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH), a decrease in the level of reactive oxygen species (ROS), and the inhibition of their ferroptosis. In addition, ChIP-qPCR experiments confirmed that Fra-1 binds to the promoter of glucose-6-phosphate dehydrogenase (G6PD), a key rate-limiting enzyme of the PPP, and transcriptionally regulates its expression, which in turn activates the PPP and promotes chemotherapy resistance in GC cells. Conclusion: Our research findings suggest that Fra-1 activates the PPP by upregulating G6PD transcriptional activity and inhibiting its ubiquitination level, inhibiting ferroptosis in GC cells and inducing chemoresistance. This provides an experimental basis for screening potential molecular targets for chemotherapy resistance in GC patients.

Tumor-secreted exosomes are heterogeneous multi-signal messengers that support cancer growth and dissemination by mediating intercellular crosstalk and activating signaling pathways. Distinct from previous reviews, we focus intently on exosome-therapeutic resistance dynamics and summarize the new findings about the regulation of cancer treatment resistance by exosomes, shedding light on the complex processes via which these nanovesicles facilitate therapeutic refractoriness across various malignancies. Future research in exosome biology can potentially transform diagnostic paradigms and therapeutic interventions for cancer management. This review synthesizes recent insights into the exosome-driven regulation of cancer drug resistance, illuminates the sophisticated mechanisms by which these nanovesicles facilitate therapeutic refractoriness across various malignancies, and summarizes some strategies to overcome drug resistance.