癌症耐药(英文)最新文献

Aim: Resistance to trastuzumab remains a major barrier to cure in early-stage HER2-positive breast cancer (HER2+ BC). We investigated the impact of genomic alterations and tumor-infiltrating lymphocyte (TIL) density on treatment resistance and survival outcomes. Methods: We retrospectively analyzed 315 patients with HER2+ BC who received adjuvant trastuzumab at Ruijin Hospital (2009-2019). Whole-exome sequencing and TIL scoring were performed on surgical specimens, and clinical and pathological data were collected. The Cancer Genome Atlas (TCGA) cohort was used for external validation. Genomic alterations and TIL density were compared between trastuzumab-sensitive and -resistant tumors. Survival analyses were conducted to identify prognostic biomarkers. Results: After a median follow-up of 109.3 months, 67 tumors (21.3%) were trastuzumab-resistant, exhibiting lower TIL density (mean 19.8% vs. 26.3%, P = 0.001), higher mutation frequencies in FLG, MAP1A, BRCA1, PTPRD, PAPPA2, NCOR2, FBXW7, MYH7, and VCAN, and more frequent alterations in the TP53/NOTCH pathways compared with sensitive tumors (all P < 0.05). A 15-gene trastuzumab response-associated gene (TRAG) signature independently predicted poorer disease-free survival (DFS) in both our cohort (HR, 3.57, P < 0.001) and the TCGA cohort (HR, 4.99, P = 0.037). A high copy number alteration burden was associated with worse overall survival (HR, 2.49, P = 0.043), whereas TIL density > 10% was associated with improved DFS (HR, 2.44, P = 0.003). A prognostic model integrating tumor size, nodal status, estrogen receptor status, TILs, and the TRAG signature showed strong discriminatory power (c-index 0.743 in the training set; 0.915 in the validation set). Conclusion: Genomic alterations and reduced TIL density underpin trastuzumab resistance. The novel TRAG signature and integrated prognostic model enhance risk stratification and may guide personalized adjuvant therapy in early-stage HER2+ BC.

Immunotherapy has emerged as a major therapeutic strategy for cancer; however, immunotherapy resistance remains a significant challenge. Hypoxia, a key hallmark of the tumor microenvironment resulting from the imbalance between the high oxygen demand of rapidly proliferating cancer cells and the limited supply from abnormal blood vessels, plays a central role in driving immunotherapy resistance. Hypoxia-inducible factor-1α (HIF-1α) and its downstream signaling pathways contribute to this resistance by promoting macrophage polarization toward the protumorigenic M2 phenotype, inducing T cell exhaustion, facilitating immune evasion, enhancing angiogenesis, and activating other resistance mechanisms. The review highlights the mechanisms by which hypoxia regulates resistance to immunotherapy and provides a comprehensive overview of nanotechnology-based strategies designed to counteract hypoxia-induced resistance. Finally, the prospects and challenges of translating nanomedicine-based drug delivery systems into clinical practice for overcoming immunotherapy resistance are outlined.

Aim: Dysregulation of tumor-suppressive pathways can lead to constitutive activation of multiple oncogenic signaling cascades. Such overactivation makes cancer cells highly dependent on these pathways, creating potential therapeutic vulnerabilities. Based on our previous findings and current data, genetic knockout of ATPase H⁺ transporting V0 subunit D1 (ATP6V0D1) - a key mediator of alkaliptosis - induces hyperactivation of oncogenic pathways, including signal transducer and activator of transcription 3 (STAT3)-mediated lysosomal pH regulation and AKT serine/threonine kinase (AKT) signaling. It also alters cellular responses to cryptotanshinone therapy. This study aimed to investigate how ATP6V0D1 deficiency reshapes oncogenic signaling networks and cellular heterogeneity in pancreatic ductal adenocarcinoma (PDAC), while evaluating therapeutic strategies that exploit alkaliptosis-related vulnerabilities. Methods: ATP6V0D1-deficient SW1990 and MIAPaCa2 cells were generated via gene knockdown. Cell viability and death following various treatments were assessed using CCK-8 and propidium iodide assays. Transcriptomic analysis was conducted to identify feedback signaling pathways, while Western blotting was used to measure expression of signaling proteins. Macropinocytosis was evaluated by TRITC-dextran uptake. Additionally, The Cancer Dependency Map (DepMap) database was analyzed to explore background differences between SW1990 and MIAPaCa2 cells. Results: ATP6V0D1 deletion led to overactivation of STAT3-mediated lysosomal pH regulation and AKT signaling; inhibition of these pathways restored alkaliptosis. Notably, cryptotanshinone selectively induced cell death in ATP6V0D1-deficient MIAPaCa2 cells but not SW1990 cells. Resistance in SW1990 cells was mediated by FGFR2 upregulation, which was reversed upon FGFR2 inhibition. Conclusion: ATP6V0D1 deficiency drives PDAC progression via dual mechanisms: compensatory oncogenic signaling (STAT3/AKT) and FGFR2-mediated cellular heterogeneity. While targeting these pathways may offer therapeutic potential, tumor heterogeneity remains a major clinical challenge.

Aim: Growing evidence points to non-genetic mechanisms underlying long-term resistance to cancer therapies. These mechanisms involve pre-existing or therapy-induced transcriptional cell states that confer resistance. However, the relationship between early transcriptional responses to treatment and the eventual emergence of resistant states remains poorly understood. Furthermore, it is unclear whether such early resistance-associated transcriptional responses are evolutionarily conserved. In this study, we examine the similarity between early transcriptional responses and long-term resistant states, assess their clinical relevance, and explore their evolutionary conservation across species. Methods: We integrated datasets on early drug responses and long-term resistance from multiple cancer cell lines, bacteria, and yeast to identify early transcriptional changes predictive of long-term resistance and assess their evolutionary conservation. Using genome-wide CRISPR-Cas9 knockout screens, we evaluated the impact of genes associated with resistant transcriptional states on drug sensitivity. Clinical datasets were analyzed to explore the prognostic value of the identified resistance-associated gene signatures. Results: We found that transcriptional states observed in drug-naive cells and shortly after treatment overlapped with those seen in fully resistant populations. Some of these shared features appear to be evolutionarily conserved. Knockout of genes marking resistant states sensitized ovarian cancer cells to Prexasertib. Moreover, early resistance gene signatures effectively distinguished therapy responders from non-responders in multiple clinical cancer trials and differentiated premalignant breast lesions that progressed to malignancy from those that remained benign. Conclusion: Early cellular transcriptional responses to therapy exhibit key similarities to fully resistant states across different drugs, cancer types, and species. Gene signatures defining these early resistance states have prognostic value in clinical settings.

Despite the development of various effective anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), therapeutic resistance remains a major challenge. Both on-target and off-target mechanisms have been identified as key contributors to resistance. With the popularization of genetic testing and the development of precision therapies, the prognosis and survival of patients with ALK-positive non-small cell lung cancer (NSCLC) have improved. However, even with second- and third-generation ALK-TKIs, overcoming resistance remains difficult. Resistance frequently arises during approved treatments, underscoring the need for further research to elucidate the molecular events and resistance mechanisms associated with ALK-positive lung cancer. The discovery of anaplastic lymphoma kinase (ALK) rearrangement as an actionable oncogenic driver in NSCLC has established a biomarker-driven treatment paradigm for advanced disease. This article summarizes current knowledge of the mechanisms of resistance to ALK-targeted therapy in lung cancer, including both primary and acquired mechanisms, treatment strategies following resistance, recent therapeutic advances, and the impact of the immune system and tumor microenvironment. A deeper understanding of ALK-targeted therapy resistance is critical for developing new treatment strategies and may provide important insights to guide the diagnosis, treatment, and management of patients with resistant ALK⁺ lung cancer.

Aim: Immune checkpoint inhibitors (ICIs) have transformed cancer therapy; however, their efficacy in head and neck cancer (HNC) remains limited, with only a minority of patients achieving durable responses. Understanding the molecular mechanisms underlying ICI resistance in HNC is therefore crucial. Methods: We conducted an integrative analysis of genomic, transcriptomic, and clinical data from 139 ICI-treated HNC patients (MSKCC cohort) and 502 treatment-naïve HNC cases (TCGA cohort). ROS1 mutation status, tumor mutational burden (TMB), neoantigen load, immune cell infiltration (via CIBERSORT), and immune-related gene expression were evaluated. Gene set enrichment analysis (GSEA) was performed to identify dysregulated pathways. Survival outcomes were assessed using Kaplan-Meier analysis and Cox regression, with statistical significance defined as P < 0.05. Results: Patients harboring ROS1 mutations exhibited significantly poorer outcomes following ICI therapy, with shorter median overall survival [OS: 5.0 vs. 11.0 months, hazard ratio (HR) = 3.22, 95%CI: 1.26-8.19, P = 0.011] compared to ROS1 wild-type counterparts. Multivariate analysis confirmed ROS1 mutation as an independent predictor of poor OS in ICI-treated patients (HR = 4.78, 95%CI: 1.70-13.43, P = 0.003). In contrast, ROS1 mutations showed no prognostic significance in the treatment-naïve TCGA-HNC cohort (P = 0.26), confirming their role as a predictive (not prognostic) biomarker for ICI response. Interestingly, despite exhibiting higher TMB and neoantigen levels, ROS1-mutant patients showed inferior survival, underscoring the context-dependent limitations of TMB as a predictive biomarker. Mechanistically, ROS1-mutant tumors displayed an immunosuppressive tumor microenvironment characterized by diminished CD8⁺ T cell infiltration, attenuated interferon-γ signaling, and downregulation of immune-related genes (CXCL9, CXCL10, IFNG, PD-L1). GSEA revealed enrichment of MYC pathway activity in ROS1-mutant tumors, which suppressed antigen presentation and T cell activation pathways. Conclusion: ROS1 mutations drive ICI resistance in HNC by promoting an immunosuppressive TME via MYC-mediated transcriptional reprogramming, impairing antigen presentation and T cell function. Incorporating ROS1 status into biomarker panels may improve patient stratification and guide combinatorial therapies targeting both immune evasion and oncogenic pathways.

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: Cisplatin serves as a primary chemotherapeutic agent in the treatment of gastric cancer (GC), but resistance to cisplatin-based chemotherapeutic regimens hampers its clinical application. Corosolic acid (CA), a natural triterpenoid, exhibits both anti-inflammatory and anti-cancer activities. However, the effect of CA on improving cisplatin resistance in GC remains unclear. The study primarily aimed to evaluate whether CA increases the therapeutic efficacy of cisplatin against GC and to reveal its underlying mechanism. Methods: Cisplatin and CA were used to treat GC cells or cisplatin-resistant AGS cells (AGS-CR), and then cell viability, apoptosis, and growth were assessed using Cell Counting Kit-8, TdT-mediated dUTP nick end labeling, and clone formation assays, respectively. Glutathione peroxidase 4 (Gpx4) expression was measured through quantitative real-time PCR and western blotting assays. Results: CA treatment induced a dose-dependent reduction in GC cell viability. The combination of cisplatin and CA resulted in enhanced cytotoxicity and pro-apoptotic effects compared to treatment with cisplatin alone. The effect of CA as a chemosensitizer in GC cells was damaged by a ferroptosis inhibitor, suggesting that CA decreased cisplatin chemoresistance by accelerating cancer cell ferroptosis. CA triggered cell ferroptosis by repressing Gpx4 expression in GC cells. Furthermore, elevated Gpx4 expression was significantly associated with poorer overall and disease-free survival. Conclusion: CA has the potential to increase cisplatin chemosensitivity in GC, and Gpx4 may represent a promising therapeutic target for its treatment.

Lactylation, a novel lactate-derived lysine post-translational modification (PTM), has emerged as a critical epigenetic regulator driving drug resistance within the tumor microenvironment (TME). This review systematically delineates the enzymatic underpinnings of lactylation, its induction via the glycolysis-lactate axis influenced by key TME features (hypoxia, inflammation), and its multifaceted roles in promoting resistance. Specifically, lactylation orchestrates transcriptional reprogramming of resistance-associated genes (e.g., oncogenes, immune checkpoints, epithelial-mesenchymal transition factors), enhances DNA damage repair capacity (e.g., via NBS1/MRE11 lactylation), activates pro-survival autophagy, and modulates immunosuppressive signaling pathways (e.g., PI3K/AKT, NF-κB, JAK/STAT). Furthermore, it facilitates critical resistance phenotypes including immune evasion, metastasis, and angiogenesis. The review summarizes emerging therapeutic strategies targeting lactylation, such as inhibition of lactate production (LDHA/LDHB), lactate transport (MCT1/4), lactyltransferases (e.g., p300), or downstream effectors, highlighting their potential to overcome multifactorial resistance. However, elucidating the context-dependent roles, crosstalk with other PTMs, and developing specific inhibitors remain crucial for translating these insights into effective clinical interventions against resistant 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.