癌症耐药(英文)最新文献

Aim: The current study aims to investigate the critical role of the focal adhesion kinase (FAK) oncogenic signaling pathway in mediating drug resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs) and evaluate the potential of two novel FAK inhibitors, 10k and 10l, as therapeutic strategies for drug resistant non-small cell lung cancer (NSCLC). Methods: EGFR-TKI resistance in NSCLC cells was developed via stepwise drug selection. Kinases/polymerase chain reaction (PCR) arrays identified key resistance determinants, while reverse transcription quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry evaluated FAK messenger RNA and phosphorylation levels. Antitumor activities were assessed using sulforhodamine-B, clonogenic, wound-healing, and apoptosis assays, spheroids and xenografts. Results: FAK was identified as a key driver of acquired resistance to EGFR-TKIs. High FAK expression predicted poor prognosis in patients treated with EGFR-TKIs. Kinase and PCR profiling confirmed elevated FAK levels as a resistance mechanism. Compounds 10k and 10l reduced phosphorylated FAK and showed strong anti-proliferative, anti-migratory, and pro-apoptotic effects in both EGFR-TKI-sensitive and -resistant cells. Notably, these compounds were shown to resensitize resistant NSCLC cells to EGFR-TKIs, with 10k inhibiting tumor growth and enhancing Osimertinib efficacy in resistant xenografts. Conclusion: These findings not only uncover a pivotal mechanism of EGFR-TKI drug resistance but also highlight innovative, promising therapeutic options for patients with therapy-refractory disease.

Drug resistance remains a significant challenge in achieving successful cancer treatment, often leading to disease recurrence and reduced patient survival. While traditional tissue biopsies provide valuable insights into tumor biology, they are invasive, infrequent, and may fail to capture the full complexity of tumor heterogeneity and dynamic molecular changes. In contrast, liquid biopsy has emerged as a minimally invasive, real-time approach for monitoring tumor evolution through the analysis of circulating biomarkers. Among these biomarkers, circular RNAs (circRNAs) - a distinct class of non-coding RNAs characterized by covalently closed-loop structures - have gained attention due to their remarkable stability, abundance in body fluids, and functional involvement in gene regulation. Increasing evidence supports the role of circRNAs in mediating drug resistance through mechanisms such as inhibition of apoptosis, epithelial-mesenchymal transition, autophagy, and drug efflux, largely via interactions with microRNAs or proteins. Advanced detection methods, including quantitative reverse transcription polymerase chain reaction, droplet digital polymerase chain reaction, and RNA sequencing, combined with computational tools, enable precise profiling of circRNAs in plasma or exosomes. CircRNA-based liquid biopsies offer a dynamic, non-invasive strategy for early detection of therapeutic resistance and may guide personalized treatment decisions. This review highlights the technological advancements, biological relevance, and clinical promise of circRNAs as circulating biomarkers, emphasizing their potential in precision oncology and future collaborative translational applications.

Immune checkpoint inhibitor (ICI) resistance often stems from intratumoral T cell dysfunction. This review focuses on both tumor-intrinsic and tumor-draining lymph node (TDLN)-centric resistance mechanisms. We detail how specific defects within TDLNs - such as impaired dendritic cell migration and the establishment of immunosuppressive niches - initiate and perpetuate systemic immune dysfunction, ultimately leading to ICI resistance. To counter these challenges, we summarize the following TDLN-targeted strategies: (1) remodeling the TDLN immunosuppressive microenvironment to restore effective antigen presentation; (2) expanding the pool of progenitor exhausted T (Tpex) cells, with a focus on their primary reservoir in TDLNs; and (3) developing adoptive cell therapies using TDLN-derived Tpex cells to generate a robust, personalized antitumor response. By repositioning TDLNs as a central therapeutic target, recent findings suggest strategies aiming to overcome resistance at its source and improve ICI clinical outcomes.

Renal cell carcinoma (RCC), the predominant form of kidney cancer, accounts for 90% of cases and poses significant clinical challenges due to frequent late-stage or metastatic presentation. Based on literature and surveillance data from 2020 to 2025, despite therapeutic advancements, metastatic RCC still exhibits a dismal 5-year survival rate. While tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor/platelet-derived growth factor pathways have been a cornerstone of RCC treatment, their efficacy is limited by acquired resistance, necessitating novel strategies to improve patient outcomes. This review synthesizes advancements from 2020 to 2025 in understanding and overcoming TKI resistance in RCC. We explored emerging mechanisms of resistance, including tumor microenvironment remodeling, metabolic reprogramming, and activation of alternative survival pathways. Furthermore, we evaluated innovative therapeutic approaches. By consolidating recent insights, this review highlights promising strategies to circumvent resistance and underscores the importance of personalized, mechanism-driven therapies. Our analysis aims to inform future research directions and clinical translation, ultimately advancing the management of TKI-resistant RCC.

Aim: Patients with KRAS-mutated colorectal cancer (CRC) frequently exhibit resistance to conventional chemotherapy and epidermal growth factor receptor (EGFR)-targeted therapies. This study investigates the role of the transcription factor KLF5 in mediating proliferation and chemoresistance in KRAS-mutated CRC, aiming to identify novel therapeutic strategies to improve treatment outcomes. Methods: We analyzed the association between KLF5 expression, KRAS mutation status, and patient prognosis using CRC tissue microarrays and public datasets. Proliferative capacity and oxaliplatin sensitivity were compared between KRAS-mutated and wild-type patient-derived organoids. RNA sequencing and CUT&Tag sequencing were employed to assess KLF5-mediated chromatin accessibility and downstream transcriptional regulation in KRAS-mutated CRC cells. In vitro and in vivo functional studies were conducted using three pairs of KRAS-mutated CRC cell lines (with KLF5 knockdown or overexpression) to evaluate KLF5's impact on proliferation, cell cycle progression, stemness, and oxaliplatin response. Results: KRAS-mutated CRC demonstrated enhanced proliferative capacity and oxaliplatin resistance, accompanied by KLF5 upregulation. In KRAS-mutated CRC cells, KLF5 promoted chromatin accessibility to initiate downstream transcription programs regulating cell cycle progression, platinum drug resistance, and apoptosis. Mechanistically, KLF5 drives oxaliplatin resistance by promoting proliferation through upregulation of the CDK4/6-Cyclin D1 axis, enhancing stemness via LGR5 and Nanog, and activating the XIAP/Bcl-2-dependent anti-apoptotic signaling pathway. In vivo experiments further confirmed that KLF5-overexpressing KRAS-mutated CRC tumors exhibited accelerated growth and reduced oxaliplatin sensitivity. Conclusion: This study reveals that aberrantly elevated KLF5 promotes proliferation and chemoresistance in KRAS-mutated CRC. Targeting KLF5 represents a promising strategy to enhance chemotherapeutic response in this aggressive CRC subtype, offering a rationale for clinical translation.

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: Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) is thought to involve both reduced drug uptake and altered molecular responses. However, the relative contribution of these mechanisms remains unclear. Methods: Two HNSCC cell lines with differing sensitivity (HNO97 and HNO41) were analyzed using cytotoxicity assays, atomic absorption spectroscopy-based quantification of intracellular cisplatin, caspase 3/7 assays, Western blotting, polymerase chain reaction (PCR)-based transcriptomic analysis of DNA damage response and cell cycle arrest pathways, and RNA-seq data from The Cancer Genome Atlas (TCGA) to characterize the resistance phenotype. Results: HNO97 (IC₅₀ = 440 µM) was 7.6-fold more resistant to cisplatin than HNO41 (IC₅₀ = 57.8 µM; P = 0.0286). After quantifying intracellular uptake (pg Pt/µg protein) and normalizing cytotoxicity to intracellular drug levels, HNO97 (IC₅₀ = 778.9 pg Pt/µg protein) remained 5-fold more resistant than HNO41 (IC₅₀ = 153.5 pg Pt/µg protein), indicating only a partial reduction in resistance (33% decrease, from 7.6-fold to 5-fold; P = 0.0286). At cisplatin concentrations yielding comparable intracellular exposure (HNO97: 440 µM; HNO41: 196 µM; both ≈ 725 pg Pt/µg protein), caspase 3/7 activation and induction of CDKN1A, GADD45A, GADD45G, and PPP1R15A were weaker in HNO97 than in HNO41. Notably, baseline expression of these genes was significantly higher in HNO97. In the TCGA cohort, multivariate analysis showed that high FANCD2 expression was associated with unfavorable recurrence-free survival in platinum-treated patients (hazard ratio = 4.0; P = 0.011), but not in those who did not receive platinum chemotherapy. Conclusion: Cisplatin resistance in HNSCC appears to be driven primarily by molecular mechanisms involving DNA damage response and cell cycle arrest pathways, rather than poor drug uptake.

Aim: This study aims to investigate the biological role of the proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14) in ovarian carcinoma drug resistance and to identify novel USP14 inhibitors (USP14i) for further preclinical development. Methods: USP14 expression was evaluated in clinical samples from 134 ovarian carcinoma patients and in a broad panel of human ovarian carcinoma cell lines. Functional studies, including gain- and loss-of-function assays, migration and invasion, and apoptosis induction assays, were conducted using cisplatin-sensitive IGROV-1 cells and their cisplatin-resistant derivative IGROV-1/Pt1. A library of 1,056 small molecules was screened using an optimized hydrolysis assay. Docking and molecular dynamics simulations were employed to predict binding modes of candidate inhibitors within the USP14 domain. Results: In clinical specimens, USP14 mRNA expression was associated with tumor grade. Exogenous overexpression of USP14 enhanced the survival of cisplatin-resistant IGROV-1/Pt1 cells, but not parental IGROV-1 cells, upon cisplatin exposure. USP14 knockdown by small interfering RNAs in resistant cells reduced aggressive features and restored cisplatin sensitivity, whereas no sensitization was observed in IGROV-1 cells. Medium-throughput screening identified five candidate molecules, among which ARN12502 showed the strongest inhibitory activity against USP14. ARN12502 exhibited an IC₅₀ of 18.4 µM, and molecular dynamics simulations confirmed stable binding in two distinct modes. In proteasome sensor-expressing cells, ARN12502 displayed proteasome-inhibitory activity. Conclusion: USP14 contributes to the aggressiveness of ovarian carcinoma, particularly to the cisplatin-resistant phenotype, and represents a relevant promising druggable target. ARN12502 serves as a starting point for chemical optimization toward the development of more potent USP14i.

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.

Hepatocellular carcinoma (HCC) poses a significant clinical burden due to its aggressive nature, profound tumor heterogeneity, and limited therapeutic efficacy. While immune checkpoint inhibitors (ICIs) have revolutionized treatment paradigms and demonstrated considerable promise, the emergence of resistance mechanisms has posed a critical challenge in contemporary clinical oncology. The accelerated development of novel agents and innovative combination strategies has further complicated this resistance landscape. In this review, we present a unique and comprehensive analysis of ICI resistance mechanisms in HCC by integrating insights into primary resistance, acquired resistance, and host-related factors. Building upon this mechanistic framework, we explore emerging therapeutic strategies to overcome ICI resistance. Furthermore, we evaluate the dual role of ICIs in HCC management - serving as a neoadjuvant therapy for transplant candidates while simultaneously posing risks of post-transplant rejection. By bridging preclinical discoveries with clinical realities, this analysis aims to inform rational therapeutic design and optimize immuno-oncology trials for HCC patients.