Search Results (8,532)

Background: Overexpression of programmed death-ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) induces immune evasion by cancer cells. Nivolumab and pembrolizumab (anti-PD-1 antibodies) are used to treat advanced non-small cell lung cancer (NSCLC). However, objective response rates are limited (20–30%), indicating that individual tumor microenvironments may differ according to immune evasion processes. Therefore, the development of biomarkers predictive of responders to immune checkpoint inhibitors is necessary. Activation of the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (NRF2/KEAP1) signaling pathway promotes lung cancer cell growth and resistance to chemotherapy, radiotherapy, targeted therapy, and PD-1/PD-L1 inhibition. The present study investigated whether NRF2 expression in NSCLC is associated with clinicopathological factors, the expression levels of intratumoral PD-L1 and CD8, and the efficacy of anti-PD-1 monotherapy. Methods: NRF2, PD-L1, and CD8 expression on tumor cells and tumor-infiltrating lymphocytes were examined by immunohistochemistry in 54 patients with advanced adenocarcinoma (N = 40) and squamous cell carcinoma (N = 14) treated with nivolumab or pembrolizumab. Histological subtypes, tumor stages, and other clinicopathological features were compared with their expression levels. Results: Weak NRF2 staining was significantly correlated with high levels of PD-L1 and CD8+ tumor-infiltrating lymphocytes, and a favorable response to treatment with nivolumab or pembrolizumab in NSCLC. Progression-free survival of patients treated with anti-PD-1 therapy differed according to the different NRF2 levels. Conclusions: NRF2 overexpression in NSCLC is associated with resistance to PD-1 blockade monotherapy. Full article

Chemotherapy resistance remains a major challenge in colorectal cancer (CRC) treatment, necessitating novel adjuvant strategies. This study employed an integrated analytical strategy combining network pharmacology, single-cell RNA sequencing (scRNA-seq) of patient-derived organoids (PDOs) and molecular dynamics simulations to identify bioactive compounds from Ganoderma lucidum and elucidate their chemo-sensitizing mechanisms. Network pharmacology identified five bioactive components of G. lucidum, corresponding to 267 potential targets. Integration with transcriptomic data, weighted gene co-expression network analysis (WGCNA), and known CRC genes refined these to 19 core targets. Cross-referencing with scRNA-seq data from irinotecan-treated PDOs pinpointed cyclin-dependent kinase 2 (CDK2) and Aurora kinase A (AURKA) as pivotal targets. Molecular dynamics simulations confirmed stable binding of the key component cerevisterol to both CDK2 and AURKA proteins, with binding free energies of −120.67 kJ/mol and −134.47 kJ/mol, respectively. In vitro cell viability assays across multiple CRC cell lines (HCT116, RKO, and HT-29) and PDOs demonstrated that cerevisterol significantly sensitized CRC cells to irinotecan (SN38). Notably, we observed that CDK2 was preferentially enriched in MSI-H tumors, whereas AURKA was enriched in MSS tumors, suggesting the potential of MSI status as a biomarker for patient stratification. Collectively, these findings identify cerevisterol as a dual-targeting natural product that modulates CDK2 and AURKA to overcome chemotherapy resistance, providing a quantitative analytical framework for discovering bioactive compounds and their molecular targets from medicinal fungi. Full article

Bispecific antibodies (bsAbs) have emerged as a novel therapeutic class in oncogene-driven non-small-cell lung cancer (NSCLC), designed to simultaneously target multiple signaling pathways and overcome resistance mechanisms associated with tyrosine kinase inhibitors (TKIs). Unlike small-molecule TKIs, bsAbs enable dual receptor blockade and immune effector engagement, offering a mechanistically distinct advantage in the context of tumor heterogeneity and bypass signaling. This review summarizes the structural and biological principles underlying bsAb design, with a focus on clinically approved agents such as amivantamab (EGFR/MET) and zenocutuzumab (HER2/HER3) and a growing pipeline of investigational agents. We evaluate key clinical evidence from Phase I-III trials including CHRYSALIS, PAPILLON, MARIPOSA, MARIPOSA-2 and eNRGy, and compare the efficacy, toxicity, and CNS penetration profile of bsAbs relative to TKIs and antibody–drug conjugates (ADCs). While bsAbs demonstrate meaningful clinical activity, particularly in TKI-resistant disease and molecularly defined subsets such as EGFR exon 20 insertions and NRG1 fusions, their limitations, including intravenous administration, increased immune-mediated and thromboembolic toxicity, currently preclude replacement of TKIs in most settings. Collectively, available evidence supports a complementary role for bsAbs within evolving multimodal treatment paradigms, particularly in combination strategies. Future directions include biomarker-driven patient selection, improved drug engineering and integration into adaptive therapeutic sequencing frameworks. Full article

Cancer accounts for approximately ten million deaths annually. The majority of these are attributable to resistance-driven tumor progression and metastasis. Although increasingly effective, precise, and selective therapeutic strategies are being developed, cancer cells retain the capacity to dynamically alter their phenotype and evade treatment. Traditional in vitro approaches rely heavily on cell line monocultures; however, their limited clinical translatability has driven the development of more advanced model systems. Three-dimensional in vitro models, including spheroids, organoids, and bioprinted tissues, provide more physiologically relevant and rapid insights, but fail to capture systemic pharmacodynamics and anatomical complexity. Emerging in vivo models, such as genetically engineered mouse models (GEMMs) of carcinogenesis and patient-derived xenografts (PDXs), as well as their derived organoids, provide a more comprehensive understanding of tumor biology. The preservation of tumor heterogeneity, microenvironment, and drug sensitivity profiles has positioned PDX models as widely used platforms in both drug development and therapy response prediction. Despite limitations—including variable engraftment rates, genetic drift, lack of fully functional immune systems, ethical concerns, and high costs—PDX models, when integrated with complementary techniques, contribute significantly to identifying novel therapeutic targets and combinations. Moreover, they support clinical decision-making by enabling drug response prediction based on genetic landscapes and co-clinical response data. Full article

Background: Due to the serious side effects and the resistant phenotype acquired by tumors, cisplatin has limited clinical efficacy. The current study aims to investigate the potential of disulfide-bridged phthalocyanines to make breast cancer cells (MCF-7) more sensitive to cisplatin. For this purpose, a novel disulfide-bridged dimeric phthalocyanine complex with a therapeutically active wavelength absorbance value that is activatable in cancer cells was synthesized and encapsulated in liposome nanoparticles. Methods: The synthesized phthalocyanine was characterized using FTIR, UV–visible, and MALDI-TOF-MS techniques; liposome nanoparticles containing the synthesized phthalocyanine were characterized using a particle size analyzer and were tested on MCF-7 breast cancer cell lines using MTT and flow cytometric assays. Results: The results have illustrated that GSH cleavages disulfide bonds of the synthesized disulfide-bridged dimeric phthalocyanine complex with quite favorable characteristics for photodynamic therapy, such as a therapeutically active wavelength absorbance value (685 nm), and disulfide-bridged phthalocyanine (ASG20)-containing liposome nanoparticles have quite favorable characteristics (average size of 167.6 nm and polydispersity index of 0.108) for biomedical applications. As evidenced by MTT and flow cytometric assays, by causing extra decreases in the viability of breast cancer cells (p < 0.01), pre-treatment of the breast cancer cells with photodynamic therapy using the activatable liposome nanoparticles significantly (p < 0.01) enhanced the anticancer activity of cisplatin in high and low doses. Conclusions: In conclusion, the activatable liposome nanoparticles containing disulfide-bridged dimeric phthalocyanine complexes can enable much more effective cisplatin-based therapies for breast cancer by overcoming the handicaps of cisplatin, drug resistance (by decreasing intracellular GSH levels), and serious side effects (by enabling the usage of lower doses of cisplatin in chemotherapy). Full article

Lung cancer remains the leading cause of cancer-related death, and, despite significant advancements in targeted therapy and immunotherapy, survival for patients with advanced non-small cell lung cancer (NSCLC) remains poor. An emerging area of interest is the role of epigenetic modifiers in both the pathogenesis and treatment of NSCLC. Herein, we review a selected group of chromatin-modifying genes implicated in NSCLC, organized by their function as writers (KMT2A, SETD2, and EZH2), erasers (the KDM2, KDM5, and KDM6 demethylase families), and readers (the SWI/SNF subunits SMARCA4 and ARID1A). Writers deposit activating or repressive marks on histones to regulate gene transcription, erasers remove these marks, and readers reposition nucleosomes and control DNA accessibility. Dysregulation of these genes has been associated with tumor proliferation, metastasis, treatment resistance, and altered response to immune checkpoint blockade in NSCLC. Research within this topic is emerging, and these genes represent promising potential therapeutic avenues as well as potential biomarkers. Finally, we review the clinical trials involving targeting these genes available in the current literature. The number of NSCLC-specific trials remains limited, with the most active development in SMARCA2 inhibitors for SMARCA4-mutated tumors and EZH2 inhibitors given in tandem with PD-1 blockade. We hope this review is hypothesis-generating for ongoing investigation into the role of epigenetic modifiers in NSCLC and their potential to expand the therapeutic armamentarium available for this disease. Full article

Acute myeloid leukemia (AML) is a genetically and biologically heterogeneous hematologic neoplasm that arises from the clonal transformation of hematopoietic progenitor cells. AML cells undergo extensive metabolic reprogramming to sustain proliferation, survival, and adaptation to therapeutic stress. Among these alterations, cholesterol metabolism has emerged as a critical determinant of leukemic cell fitness. AML cells enhance cholesterol biosynthesis, uptake, trafficking, and storage, generating a dynamic network that supports membrane organization, mitochondrial function, oncogenic signaling, and resistance to therapy. Beyond these tumor-intrinsic roles, accumulating evidence indicates that cholesterol and its metabolites actively shape communication between leukemic and immune cells, influencing immune checkpoint expression, inflammatory signaling, and antitumor immune responses within the bone marrow microenvironment. This narrative review examines the mechanisms underlying cholesterol reprogramming in AML and discusses how alterations in cholesterol homeostasis integrate metabolic adaptation with immune regulation. Particular emphasis is placed on the interplay between cholesterol metabolism, leukemic stem cell persistence, therapeutic resistance, and immune dysfunction. Emerging therapeutic strategies targeting cholesterol-related pathways are also considered. Collectively, these findings position cholesterol metabolism as a central interface between tumor-intrinsic biology and immune crosstalk, highlighting its potential as a therapeutic vulnerability in AML. Full article

Bladder cancer is the fifth most common cancer in the United States, causing approximately 17,000 deaths annually. Due to its vast genetic and molecular heterogeneity, presentation, prognosis, and therapeutic response vary greatly between individuals. To improve patient outcomes, there is a need for better drug-screening platforms. The genetic heterogeneity of bladder cancer often leads to chemotherapy resistance or low response rates. Moreover, chemotherapies are often contraindicated in patients with select comorbidities. Organoids offer a better option to replicate the tumor microenvironment than traditional 2D cell cultures, improving drug development and personalized therapy. In this study, we bioprinted gelatin-methacrylol (GelMA)-based organoids containing bladder cancer cell lines of different grades to model muscle-invasive bladder cancer. In the organoids, we observed distinct grade-dependent tumor proliferation and progression dynamics. Treatment with standard-of-care chemotherapies revealed a grade-dependent tumor response consistent with in vivo patient data, highlighting the suitability of these organoids for rapid, reliable drug testing. Lastly, we used the organoids to test LCI139, a novel small-molecule inhibitor of PI3K, CDK4/6, and CDK9 designed for the treatment of epithelial cancers, underscoring the potential of our model to evaluate the efficacy of newly developed drugs. The ability to quickly biofabricate reproducible bladder cancer organoids that are adaptable to different tumor grades represents a novel strategy to create an in vitro platform with strong potential to predict treatment outcomes of bladder cancer patients. Full article

Vasculogenic mimicry (VM) is a non-endothelial mode of tumor vascularization in which aggressive cancer cells form vessel-like networks that support microcirculation, metastasis, and resistance to anti-angiogenic therapies. VM is particularly prominent in triple-negative breast cancer (TNBC), but its molecular regulators remain incompletely understood. Focal adhesion kinase (FAK) and its paralog, proline-rich tyrosine kinase 2 (Pyk2), are closely related non-receptor tyrosine kinases implicated in epithelial-to-mesenchymal transition (EMT), invasion, and metastasis in TNBC. However, their roles in VM have not been defined. Here we perform transcriptomic analysis of FAK and Pyk2 clinical expression patterns using TNMplot V2, DepMap, and patient cohort datasets to systematically dissect the distinct contributions of FAK and Pyk2 to VM in TNBC. Our in vitro tube formation assay shows that in TNBC cells, knockdown of FAK, but not Pyk2, results in failure to form robust 3D vessel-like networks in Matrigel. Similarly, overexpression of Pyk2, but not FAK, in TNBC cells results in poor vessel-like network formation. Consistent with these findings, analysis of two independent patient cohorts (TCGA-BRCA and METABRIC) revealed selective upregulation of FAK in TNBC, while Pyk2 was inversely associated with vasculogenic-mimicry-associated gene expression, supporting the opposing roles of the two kinases in patient tumors. Taken together, these findings establish that FAK and Pyk2 govern VM through non-redundant, kinase-specific, and functionally opposed mechanisms: FAK acting as a positive regulator of VM, and Pyk2 as a context dependent suppressor of VM at elevated levels. These results nominate FAK as a candidate target for suppressing VM-driven tumor perfusion in TNBC and suggest that dual FAK/Pyk2 inhibition warrants caution hypotheses that remain to be tested pharmacologically. Full article

Background: CDK4/6 inhibitors induce G1/S cell-cycle arrest in bladder cancer; however, adaptive resistance limits their therapeutic efficacy. The role of the m⁶A reader IGF2BP3 in regulating sensitivity to CDK4/6 inhibition remains largely unknown. Methods: Transcriptomic profiling was performed in palbociclib-treated bladder cancer cell lines (T24, RT112, and UMUC-3) to identify m⁶A regulators associated with drug response. The expression and clinical significance of IGF2BP3 were evaluated using The Cancer Genome Atlas (TCGA) data and an independent clinical cohort. Gain- and loss-of-function assays were conducted to investigate the effects of IGF2BP3 on cell proliferation and cell-cycle progression. Mechanistic studies, including RNA-binding, mRNA stability, ubiquitination, and in vivo tumorigenesis assays, were performed to elucidate the underlying regulatory network. Results: IGF2BP3 was identified as the only m⁶A regulator differentially expressed following palbociclib treatment. IGF2BP3 expression was significantly elevated in bladder cancer tissues compared with normal tissues and was associated with poor prognosis and Ki67 positivity. Functionally, IGF2BP3 overexpression (OE) promoted G1/S transition, increased MYC and downstream cell-cycle regulators, and partially rescued palbociclib-induced cell-cycle arrest, whereas IGF2BP3 knockdown (KD) suppressed cell proliferation in an MYC-dependent manner. Mechanistically, IGF2BP3 bound to MYC mRNA in an m⁶A-dependent manner and enhanced its stability. Furthermore, MKRN2 was identified as an E3 ubiquitin ligase that directly interacted with IGF2BP3, promoted its ubiquitination, and facilitated its proteasomal degradation. In vivo, MKRN2 co-overexpression attenuated IGF2BP3-driven tumor growth and synergized with palbociclib to maximally suppress tumor volume, reduce MYC and Ki67 expression, and induce apoptosis. Conclusions: These findings establish the MKRN2–IGF2BP3–MYC axis as a critical regulator of CDK4/6 inhibitor sensitivity in bladder cancer. Targeting IGF2BP3 or enhancing MKRN2 activity may represent a promising strategy to overcome adaptive resistance and improve the therapeutic efficacy of CDK4/6 inhibitors. Full article

Background/Objectives: Curcumin shows broad anticancer activity but limited clinical success as a standalone agent because of poor bioavailability and inconsistent tumor exposure. This review introduces the concept of curcumin as a molecular synergy amplifier and proposes that successful combinations depend on three interdependent determinants: mechanistic complementarity, suppression of adaptive resistance networks, and pharmacokinetic synchronization. Methods: Evidence on combinations with chemotherapeutics, natural bioactives, and nanotechnology-enabled delivery systems was critically evaluated, with emphasis on mechanism, resistance reversal, drug ratio, administration sequence, and tumor exposure. Results: Curcumin enhances therapeutic efficacy by sensitizing cancer cells, suppressing adaptive resistance pathways, targeting cancer stemness, and promoting multiple forms of programmed cell death. Importantly, analysis of current evidence indicates that therapeutic success depends not only on molecular synergy but also on pharmacokinetic synchronization between curcumin and partner agents. Many combinations demonstrating strong in vitro synergy fail to translate in vivo because optimal drug ratios, timing, and tumor exposure cannot be maintained. Nanotechnology-based co-delivery systems partially overcome these limitations through synchronized delivery and controlled release. Conclusions: Curcumin should be viewed as a molecular synergy amplifier whose clinical utility depends on mechanistic complementarity and pharmacokinetic synchronization with co-administered therapies. This framework provides a rationale for the design of next-generation curcumin-based combination therapies and identifies key priorities for clinical translation. Full article

Cartilage oligomeric matrix protein (COMP) influences extracellular matrix remodeling. We investigated its clinical, prognostic, and immunomodulatory significance in colorectal cancer (CRC). COMP was quantified via ELISA in 107 paired CRC and normal tissues. Expression was correlated with clinicopathological features, mutational profiles, microsatellite instability (MSI), tumor-infiltrating lymphocytes (TILs), immune checkpoints, and multiplex cytokine networks. For transcriptomic validation, the FieldEffectCrc dataset was used for Gene Set Enrichment Analysis (GSEA), and The Cancer Genome Atlas (TCGA) CRC cohort for survival analysis. COMP was significantly upregulated in CRC tissues (p < 0.001) and correlated with advanced T, N, and overall pathological stages (all p < 0.05, tau = 0.18, 0.21, and 0.23, respectively). High COMP expression was linked to restricted immune infiltration (reduced stromal TILs, p < 0.05, tau = −0.23), elevated levels in microsatellite stable (MSS) compared to MSI tumors (p < 0.01), and correlated positively with immune exhaustion markers (T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), galectin-9 (GAL9), sialic acid-binding Ig-like lectin 9 (SIGLEC9)). Transcriptomic data linked high COMP to worse disease-specific and progression-free survival, and enrichment in pro-tumorigenic pathways (epithelial-to-mesenchymal transition, angiogenesis, IL-6 signaling). COMP upregulation defines an immunosuppressive microenvironment in CRC, particularly in MSS tumors. It represents an important prognostic biomarker and potential therapeutic target for overcoming immunotherapy resistance. Full article

Malignant gliomas are highly aggressive primary brain tumors for which the therapeutic efficacy of cisplatin is frequently limited by intrinsic or acquired drug resistance. Despite advances in adjuvant therapies, overcoming chemoresistance remains a major challenge in the treatment of these malignancies. Emerging evidence indicates that long non-coding RNAs (lncRNAs), a class of non-protein-coding transcripts involved in gene regulation, play important roles in modulating treatment responses. Several lncRNAs, including differentiation antagonizing non-protein-coding RNA (DANCR), HOXD antisense growth-associated long non-coding RNA (HOXD-AS1), MEG3, MALAT1, and HOTAIR, have been implicated in pathways associated with glioma progression and therapeutic resistance. In particular, DANCR has been reported to promote cisplatin resistance in glioma cells through suppression of apoptosis and activation of pro-survival signaling pathways. This review summarizes current evidence regarding the roles of lncRNAs in cisplatin resistance, highlighting mechanisms such as regulation of drug transport, DNA damage repair, apoptosis, cancer stem-cell maintenance, and signaling pathways associated with treatment adaptation. We also discuss current limitations, challenges for clinical translation, and gaps in the existing evidence. A better understanding of lncRNA-mediated resistance mechanisms may facilitate the identification of novel therapeutic targets and inform future studies aimed at overcoming cisplatin resistance in malignant gliomas. Full article

Glioblastoma multiforme (GBM), isocitrate dehydrogenase (IDH)-wildtype, is the most aggressive primary malignant tumor of the central nervous system, characterized by poor prognosis and high recurrence rates despite standard multimodal treatment. This study investigates the molecular response of glioblastoma cells to 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT), focusing on gene expression changes associated with apoptosis, ferroptosis, and oxidative stress. Human glioblastoma T98G cells were treated with 5-ALA followed by light irradiation, and gene expression was analyzed using RT-qPCR. PDT induced moderate upregulation of pro-apoptotic genes (BAX, CASP3, FAS) alongside increased expression of the anti-apoptotic gene BCL2, indicating simultaneous activation of cell death and survival pathways. Ferroptosis-related genes showed mixed responses, with slight upregulation of ACSL4 and downregulation of GPX4, suggesting increased susceptibility to lipid peroxidation. The most significant change was observed in GCH1 expression, reflecting activation of oxidative stress response mechanisms. However, none of the observed changes reached statistical significance, likely due to the limited sample size. These findings demonstrate that PDT induces a complex and dual biological response in glioblastoma cells, involving both cytotoxic and adaptive mechanisms. This may limit therapeutic efficacy and contribute to treatment resistance. The results support the rationale for combining PDT with targeted molecular therapies aimed at inhibiting antioxidant defenses and anti-apoptotic pathways. Additionally, personalized therapeutic strategies based on tumor molecular profiles may enhance treatment outcomes. Further studies with larger sample sizes and functional validation are required to confirm these preliminary observations. Full article

Cetuximab and panitumumab are anti-EGFR monoclonal antibodies widely used for the treatment of colorectal cancers. However, due to various mechanisms of resistance to these targeted therapies, the patients’ responses vary. These resistances remain a major obstacle in treatment and overcoming them has become a key emphasis of current therapeutic strategies. Intrinsic and acquired resistance often lead to reactivation of downstream signaling pathways, mainly the RAS-RAF-MEK-ERK (MAPK pathway) and PI3K-AKT axes. Prior existing mutations in KRAS, NRAS, and BRAF result in primary resistance by constantly activating the signals, irrespective of EGFR inhibition. That said, acquired resistance manifests under therapeutic burden through the process of clonal evolution via KRAS and BRAF alterations, restoring MAPK pathway activity despite EGFR inhibition. In addition to those mutations, tumor cells exploit mechanisms independent of EGFR, such as the pathway bypass, which includes amplification of ERBB family receptors like HER2 (ERBB2) and activation of MET signaling. To overcome these resistances, novel strategies have emerged, which target multiple nodes within the oncogenic networks. Such methods include vertical pathway inhibition, multi-kinase inhibition, liquid-biopsy-guided therapy, and anti-EGFR rechallenge. Reactivation driven by secondary mutation can be prevented by targeting multiple nodes within the MAPK cascade simultaneously, which is referred to as the vertical pathway inhibition. Overall, this review underscores that overcoming therapeutic resistance requires a multidimensional approach that integrates molecular profiling, rational combination therapies, and adaptive treatment. Finally, these advances underscore the shift toward precision oncology, where therapy is tailored to tumor evolution, leading to improved response and patient outcome. Full article