癌症耐药(英文)最新文献

Aim: Glioblastoma (GBM) is the most malignant grade of glioma, characterized by high recurrence, poor prognosis, and frequent chemoresistance. There is an urgent need for alternative treatment strategies. In this study, we evaluated the effects of THZ2, a covalent inhibitor targeting the super-enhancer (SE) component CDK7, on GBM growth and chemoresistance. We also used another SE inhibitor, JQ1, to further validate the inhibitory effects of targeting SEs in GBM, thereby providing new treatment strategies for patients. Methods: A variety of in vitro and in vivo assays were performed to explore the anti-GBM effects of SE inhibitors. We assessed the effects of SE inhibitors in combination with temozolomide (TMZ) on GBM cells and calculated the combination index. Additionally, CUT&RUN assays were conducted to examine protein-DNA interactions. Results: THZ2 inhibited the proliferation, migration, and invasion of GBM cells and induced cell cycle arrest and apoptosis. Furthermore, both THZ2 and JQ1 exhibited synergistic antitumor effects when combined with TMZ in GBM cells. Notably, THZ2 reversed TMZ resistance in GBM cells by suppressing the expression of the SE-associated gene SOX9. We also found that SOX9, CDK7, and BRD4 interact with histone H3K27ac. Conclusion: Our findings demonstrate that SE inhibitors exert antitumor effects in GBM and act synergistically with TMZ. THZ2 may enhance chemosensitivity by downregulating the SE-related gene SOX9, and it holds promise as a novel therapeutic agent for GBM patients.

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 situ ³H-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.

Antibody-Drug Conjugates (ADCs) have achieved significant success in cancer therapy by combining the targeting specificity of monoclonal antibodies with cytotoxic payloads. However, the concomitant issue of drug resistance has become increasingly prominent, with primary mechanisms including alterations in target antigen expression, impaired drug transport, and inhibition of cell death pathways. ADCs have also shown emerging therapeutic potential in the treatment of autoimmune diseases; for instance, ABBV-3373 has achieved initial success in this area, yet it also faces unique challenges such as the safety of long-term administration, immunogenicity, and heterogeneity of target cells. Addressing these challenges requires multidimensional innovations, including optimizing molecular design, exploring combination therapy strategies, and introducing artificial intelligence (AI)-assisted development. These efforts aim to transition ADCs from the traditional "targeted killing" paradigm to intelligent and personalized precision delivery systems, thereby offering more therapeutic options for patients with cancer and autoimmune diseases.

Hepatocellular carcinoma (HCC) is a malignant tumor originating from hepatocytes, often developing against a backdrop of chronic inflammation and liver fibrosis. The primary risk factor for HCC is cirrhosis, and early detection is crucial for improving outcomes. Despite advances in treatment, the prognosis remains poor, with a 5-year survival rate of approximately 15%-38%. Growing evidence highlights the critical role of the tumor microenvironment (TME) in modulating tumor initiation, growth, progression, and, in some cases, suppression. The TME is a complex ecosystem composed of immune cells, cancer-associated fibroblasts, extracellular matrix components, and other factors such as growth factors and cytokines. By shaping tumor cell behavior, the TME facilitates immune evasion and contributes to resistance to treatment. Tumor-associated immune cells, including regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages, contribute to immune suppression and progression. On the other hand, immune activation via immune checkpoint inhibition has shown promise in improving outcomes, especially when combined with other treatments such as transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), and systemic therapies. Studies have demonstrated the potential of targeting the TME to enhance treatment efficacy, with immune modulation emerging as a key therapeutic strategy. This review explores the complex interactions within the TME in HCC, highlighting its role in therapy resistance and immune evasion. It also discusses current therapeutic approaches to target the TME to improve clinical outcomes in HCC patients.

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.

Introduction: Prostate cancer (PCa) continues to be a significant cause of mortality among men, with treatment resistance often influenced by the complexity of the tumor microenvironment (TME). This study aims to develop an immune-centric prognostic model that correlates TME dynamics, genomic instability, and the heterogeneity of drug resistance in PCa. Methods: Multi-omics data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were integrated, encompassing transcriptomic profiles of 554 TCGA-PRAD samples and 329 external validation samples. Immune cell infiltration was assessed using CIBERSORT and ESTIMATE. Weighted gene co-expression network analysis (WGCNA) was employed to identify immune-related modules. Single-cell RNA sequencing (ScRNA-seq) of 835 PCa cells uncovered subtype-specific resistance patterns. Prognostic models were constructed using least absolute shrinkage and selection operator (LASSO) regression and subsequently validated experimentally in PCa cell lines. Results: Two immune subtypes were identified: high-risk subgroups displayed TP53 mutations, increased tumor mutation burden (TMB), and enriched energy metabolism pathways. ScRNA-seq delineated three PCa cell clusters, with high-risk subtypes being sensitive to bendamustine/dacomitinib and resistant to apalutamide/neratinib. A 10-gene prognostic model (e.g., MUC5B, TREM1) categorized patients into high/low-risk groups with distinct survival outcomes (log-rank P < 0.0001). Validation in external datasets confirmed the robust predictive accuracy (AUC: 0.854-0.889). Experimental assays verified subtype-specific drug responses and dysregulation of key model genes. Discussion: This study establishes a TME-driven prognostic framework that connects immune heterogeneity, genomic instability, and therapeutic resistance in PCa. By pinpointing metabolic dependencies and subtype-specific vulnerabilities, our findings provide actionable strategies to circumvent treatment failure, such as targeting energy metabolism or tailoring therapies based on resistance signatures.

Thyroid cancer, particularly papillary thyroid cancer (PTC), represents the most prevalent endocrine malignancy. Despite advancements in therapeutic strategies, drug resistance significantly hampers clinical outcomes. Autophagy, an evolutionarily conserved cellular degradation pathway, acts paradoxically in thyroid cancer by promoting either tumor cell survival or cell death, thus influencing therapeutic resistance. Increasing evidence highlights microRNAs (miRNAs), small non-coding RNAs, as critical regulators of autophagy through precise modulation of autophagy-related genes (ATGs) and signaling pathways. miRNA-mediated autophagy can either enhance chemotherapeutic efficacy or facilitate resistance, depending on the cellular context and miRNA targets. This review summarizes recent insights into miRNA-autophagy interactions underlying drug resistance in thyroid cancer, emphasizing key miRNAs, including miR-125b, miR-144, miR-30d, and miR-9-5p. Understanding the complex regulatory networks connecting miRNAs and autophagy provides promising avenues for developing novel therapeutic strategies to overcome resistance in refractory thyroid cancer.

Antibody-drug conjugates (ADCs), inspired by Paul Ehrlich's "magic bullet" concept to target cancer cells with cytotoxic drugs while sparing healthy cells, represent a transformative approach in breast cancer therapy. From early agents (e.g., gemtuzumab ozogamicin) to second-generation trastuzumab emtansine (T-DM1) and third-generation trastuzumab deruxtecan (T-DXd)/disitamab vedotin (RC48), ADCs have demonstrated significant clinical benefits, including improved progression-free survival (PFS) and overall survival (OS) in breast cancer, with several approved for clinical use. Ongoing preclinical and clinical studies are rigorously exploring ADC combinations with molecular targeted agents, chemotherapy, and immunotherapy. However, de novo and acquired resistance remains a critical barrier to maximizing therapeutic efficacy. This review summarizes ADC mechanisms and clinical outcomes in breast cancer, explores resistance mechanisms, and dissects the biological rationale for combination strategies, aiming to identify novel payloads that enhance patient outcomes.

Aim: The fibroblast growth factor receptor (FGFR) family receptors regulate cell proliferation, survival, and migration and are linked to cancer drug resistance. FGFR gene family alterations have been found in multiple adult cancers, for which FGFR inhibitors are in various stages of clinical development. This study aimed to delineate the FGFR alterations in pediatric tumors and provide a preclinical rationale for developing FGFR inhibitors for select pediatric patients. Methods: The prevalence of FGFR alterations in pediatric cancers was calculated from databases with available pediatric tumor data. Effects of the pan-FGFR inhibitor infigratinib (BGJ398) on pediatric cancer cell line viability and migration were evaluated by continuous live cell imaging and compared to FGFR gene expression. Effects on cell death and signaling pathway activity were evaluated by live cell imaging and Western blots. Results: Overall rates of FGFR1-4 gene alterations in pediatric cancers were rare, and the mutation profile substantially differs from that of adult tumors. Although FGFR genomic alterations are rare in pediatric neuroblastoma tumors, overexpression of FGFR1-4 is observed in tumor subsets and is associated with outcomes. Dose-dependent inhibition of cell proliferation and migration and promotion of cell death were achieved with BGJ398 treatment in neuroblastoma cell lines, accompanied by inhibition of RAS-MAPK pathway activity and induction of apoptosis. Conclusion: Adult and pediatric cancers share common mechanisms of FGFR activation but differ in overall alteration rates and relative abundance of specific aberrations. Preliminary experimental data indicate the therapeutic potential of FGFR inhibitors and suggest mechanisms of resistance in the treatment of pediatric cancers.