Anti-cancer Drugs[JOURNAL]
Sun
200 papers
A genome-wide screen identified ARHGAP35 as a regulator of regorafenib resistance in liver cancer.
Chen K, Zhang M, Liu Y … +4 more , Dong Z, Liang Y, Zeng J, Liu J
Anticancer Drugs · 2026 Feb · PMID 41176659 · Publisher ↗
Regorafenib, a multikinase inhibitor, is widely used to treat hepatocellular carcinoma. However, chemoresistance poses a significant challenge to its long-term efficacy. This study conducted a genome-wide CRISPR/Cas9 kno...
Regorafenib, a multikinase inhibitor, is widely used to treat hepatocellular carcinoma. However, chemoresistance poses a significant challenge to its long-term efficacy. This study conducted a genome-wide CRISPR/Cas9 knockout screen in liver cancer cell lines to identify key regulators of regorafenib resistance and elucidate the underlying molecular mechanisms. The screen identified ARHGAP35 as a critical negative regulator of regorafenib resistance. ARHGAP35 depletion conferred resistance in HepG2 and Huh7 cells, while regorafenib-resistant variants (HepG2-R and Huh7-R) exhibited decreased ARHGAP35 expression. Reintroducing ARHGAP35 restored drug sensitivity. Further analysis revealed that reduced ARHGAP35 expression facilitated epithelial-mesenchymal transition (EMT) by activating the RhoA signaling pathway. Notably, RhoA inhibition reversed EMT and restored regorafenib sensitivity. These findings highlight ARHGAP35 as a key modulator of regorafenib resistance through RhoA suppression, offering potential therapeutic targets to combat chemoresistance in liver cancer.
Multifaceted transcriptional reprogramming supports oxaliplatin chemoresistance in colorectal cancer cells.
Calibasi-Kocal G, Kurter H, Isik Z
Anticancer Drugs · 2026 Jan · PMID 41175392 · Publisher ↗
Oxaliplatin resistance remains a critical barrier to effective colorectal cancer treatment. The molecular mechanisms underlying this resistance are not fully understood, highlighting the need to define the transcriptiona...
Oxaliplatin resistance remains a critical barrier to effective colorectal cancer treatment. The molecular mechanisms underlying this resistance are not fully understood, highlighting the need to define the transcriptional alterations that contribute to therapeutic failure. Accordingly, a comparative transcriptome analysis was performed on oxaliplatin-resistant colorectal cancer cells (HCT-116-ROx) and their parental counterparts (HCT-116) using RNA sequencing in this study. Differentially expressed gene (DEG) analysis was conducted using a quasi-likelihood negative binomial model. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were carried out using the topGO and clusterProfiler packages, respectively. To confirm the robustness of the transcriptomic data, the genes with the most significant expression changes, based on false discovery rate-adjusted P value less than 0.05 and a |logFC| > 2 thresholds, were selected for validation by quantitative real-time PCR (qRT-PCR). A total of 313 DEGs were identified, including ALDH3A1 and TACSTD2 (upregulated) and IFITM1 (downregulated); these three genes were chosen for validation by qRT-PCR. Gene Ontology enrichment revealed significant changes in cell motility, redox regulation, and extracellular matrix remodeling. KEGG analysis indicated upregulation of ferroptosis, glutathione metabolism, and lysosome-related pathways, and downregulation of p53 signaling, oxidative phosphorylation, and cancer-specific pathways. Oxaliplatin-resistant colorectal cancer cells undergo multifaceted transcriptional reprogramming that promotes redox homeostasis, metabolic adaptation, and structural plasticity while suppressing apoptotic and mitochondrial functions. These changes support chemoresistance and may represent potential therapeutic targets to restore drug sensitivity.
Adiponectin Receptor 1-vascular endothelial growth factor axis mediates resistance to epidermal growth factor receptor-targeted therapy in nasopharyngeal carcinoma.
Cheng Z, Peng X, Wu S … +3 more , Li W, Liu X, Zhang G
Anticancer Drugs · 2026 Feb · PMID 41175391 · Publisher ↗
Nasopharyngeal carcinoma (NPC) is highly prevalent in Southeast Asia and southern China, with most patients diagnosed at advanced stages. Although epidermal growth factor receptor (EGFR)-targeted therapies have shown cli...
Nasopharyngeal carcinoma (NPC) is highly prevalent in Southeast Asia and southern China, with most patients diagnosed at advanced stages. Although epidermal growth factor receptor (EGFR)-targeted therapies have shown clinical promise, their long-term efficacy is limited. This study explores the regulatory role of AdipoR1 in EGFR-targeted therapy response and evaluates adiponectin as a potential strategy to overcome treatment resistance. NPC cell lines (5-8F and CNE1) were treated with nimotuzumab for short (24 h) and long (72 h) durations. mRNA and protein expression of vascular endothelial growth factor (VEGF), AdipoR1/R2, and other pathway components were assessed using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting. Adiponectin was applied to explore its regulatory role in VEGF expression and EGFR signaling. Prolonged treatment of NPC cells with nimotuzumab inhibited EGFR downstream signaling [protein kinase B, mammalian target of rapamycin (mTOR), extracellular signal-regulated kinase], reduced cell invasion and migration initially, but invasive capacity gradually recovered over time. VEGF expression remained unchanged at 24 h but significantly increased after 72 h, promoting angiogenesis in cocultured HUVECs. Long-term nimotuzumab exposure downregulated AdipoR1 expression, while adiponectin restored AdipoR1 and VEGF levels with decreased mTOR expression, not EGFR, indicating that the mTOR pathway may mediate this regulation. In addition, nimotuzumab elevated the expression of lipid metabolism-related genes, FABP4 and CD36, which was mitigated by A-PN cotreatment. Prolonged EGFR-targeted therapy in NPC upregulates VEGF via AdipoR1 downregulation, reducing treatment efficacy. Adiponectin restores AdipoR1, suppresses VEGF, and reverses this effect, possibly through mTOR inhibition, suggesting a potential strategy to improve long-term therapeutic outcomes.
Low relative dose intensity adjuvant chemotherapy in elderly patients with breast cancer: predictors and impact on survival.
Ramos-Esquivel A, Romero-Orocu D, Mora-Hidalgo R
Anticancer Drugs · 2026 Feb · PMID 41175390 · Publisher ↗
Chemotherapy improves outcomes in patients with high-risk early or locally advanced breast cancer, but older adults often experience higher toxicity that leads to treatment delays, dose reductions, and reduced relative d...
Chemotherapy improves outcomes in patients with high-risk early or locally advanced breast cancer, but older adults often experience higher toxicity that leads to treatment delays, dose reductions, and reduced relative dose intensity (RDI). This study examined predictors of low RDI and its impact on overall survival (OS) in women aged over 65 years treated with neoadjuvant or adjuvant chemotherapy at San Juan de Dios Hospital (Costa Rica) between November 2018 and April 2023. A total of 264 patients (mean age: 70.1 years) were included. Nearly one-third had a Charlson Comorbidity Index (CMI) greater than 6. Tumor subtypes were hormone receptor (HR)+/ human epidermal growth factor receptor (HER2)-(48.9%), HR+/HER2+ (15.9%), HR-/HER2+ (33%), and triple-negative (17.8%). Most patients (68.6%) received anthracycline-based regimens. Overall, 17.4% had an RDI below 80%. After a median follow-up of 54.6 months, 56 deaths were recorded. Low RDI was significantly associated with worse OS [hazard ratio: 1.79, 95% confidence interval (CI): 1.02-3.13; P = 0.04]. Independent predictors of low RDI were anthracycline-based therapy [odds ratio (OR): 4.76, 95% CI: 2.17-9.09], CMI greater than 6 (OR: 2.13, 95% CI: 1.02-4.54), and age more than 70 years (OR: 2.38, 95% CI: 1.14-5.01). These findings suggest that advanced age, comorbidities, and anthracycline regimens increase the risk of reduced RDI, which negatively impacts survival. Supportive measures are critical to maintain chemotherapy intensity in older women.
Temsirolimus targets chemoresistant uveal melanoma via mammalian target of rapamycin inhibition and enhances chemotherapy.
Huang Q, Jiang X, Tao N
Anticancer Drugs · 2026 Feb · PMID 41175389 · Publisher ↗
Chemotherapy resistance remains a major challenge in the treatment of uveal melanoma, necessitating the identification of novel therapeutic strategies. In this study, we established chemoresistant uveal melanoma cell lin...
Chemotherapy resistance remains a major challenge in the treatment of uveal melanoma, necessitating the identification of novel therapeutic strategies. In this study, we established chemoresistant uveal melanoma cell lines by exposing parental cells to dacarbazine, cisplatin, or gemcitabine and performed high-throughput drug screening incorporating normal human epidermal melanocytes (NHEMs) as a normal control to assess both efficacy and selectivity. Our screening identified temsirolimus and selumetinib as top candidates, with temsirolimus exhibiting strong tumor-selective cytotoxicity. Further in-vitro studies confirmed that temsirolimus induced apoptosis and suppressed clonogenic potential in chemoresistant uveal melanoma cells while having minimal effects on NHEM. Combination studies demonstrated synergy between temsirolimus and cisplatin or gemcitabine, reinforcing its role as an effective chemosensitizer. In a chemoresistant uveal melanoma xenograft model, temsirolimus significantly inhibited tumor growth without inducing systemic toxicity, as evidenced by stable biochemical markers of organ function. Mechanistically, temsirolimus downregulated mammalian target of rapamycin (mTOR) signaling, as indicated by reduced p-mTOR, p-S6, and p-4EBP1 expression in tumor tissues. These findings demonstrate that temsirolimus selectively targets chemoresistant uveal melanoma cells, enhances chemotherapy efficacy, and suppresses tumor growth via mTOR inhibition, supporting its potential clinical application as a novel therapeutic strategy for chemoresistant uveal melanoma.
Real-world treatment patterns and survival outcomes in patients with metastatic castration-resistant prostate cancer in France: lessons from the prospective OPALE study.
Papet J, Augusto-Pelegrin L, Christy F … +4 more , Lequesne J, Di Fiore F, Joly F, Pfister C
Anticancer Drugs · 2025 Nov · PMID 41082589 · Publisher ↗
In metastatic castration-resistant prostate cancer (mCRPC), several treatments are available, including androgen-receptor pathway inhibitors (ARPis) and chemotherapy (CT). There is a lack of real-world prospective data o...
In metastatic castration-resistant prostate cancer (mCRPC), several treatments are available, including androgen-receptor pathway inhibitors (ARPis) and chemotherapy (CT). There is a lack of real-world prospective data on treatment sequences and survival. The aim of the study was to evaluate overall survival (OS) in real-world conditions for patients treated for mCRPC. The OPALE study is a French prospective observational multicentre study. We included between 2018 and 2023, 212 patients undergoing first or second-line treatment for mCRPC. The primary outcome was the median OS, defined as the time between mCRPC diagnosis and death from any cause. The key secondary endpoints included OS according to therapeutic sequences, progression-free survival, response, and toxicities. Survival analysis was estimated using the Kaplan-Meier method and compared using the log-rank test. Associations between treatments and survival were assessed using Cox models. The 212 patients received first-line treatment (L1), 130 second-line (L2), 85 third-line (L3), and 51 fourth-line (L4). Most patients received ARPis in L1 (85.8%) and then chemotherapy in L2 (56.2%) and L3 (55.3%). The mean duration of follow-up was 31.8 months. Median OS was 46.4 months [95% confidence interval (CI): 35.9-53.8]. Our data did not significantly demonstrate the superiority of one therapeutic sequence over the others. Limitations are the observational design and the lack of statistical power. The OPALE study provided valuable data on the real-life management of mCRPC, contributing to a better understanding of current practice. We did not identify any optimal regimen, reflecting the evolution of knowledge and recent recommendations.
Circular RNA SMARCA5 inhibits cholangiocarcinoma via microRNA-95-3p/tumor necrosis factor receptor associated factor 3 axis: Erratum.
Wang G, Gao X, Sun Z … +4 more , He T, Huang C, Li S, Long H
Anticancer Drugs · 2025 Oct · PMID 40937530 · Full text
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LncRNA FOXP4-AS1 silencing inhibits metastasis and epithelial-mesenchymal transition in nasopharyngeal carcinoma via miR-136-5p/MAPK1: Erratum.
Yan J, Zhou Q
Anticancer Drugs · 2025 Oct · PMID 40937529 · Full text
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Pembrolizumab treatment in SMARCA4-deficient nonsmall cell lung cancer: high tumor mutational burden and programmed death-ligand 1(+) expression on circulating tumor cells for real-time monitoring: a case report.
Deng Y, Huang Y, Cai S … +7 more , Huang C, Liu W, Jia R, Sui Z, Zou H, Yu Z, Guo X
Anticancer Drugs · 2025 Nov · PMID 40928867 · Full text
Nonsmall cell lung cancer (NSCLC) with SMARCA4 deficiency represents a rare subset of lung tumors characterized by early metastasis, poor response to chemotherapy, and unfavorable prognosis. Established therapy strategie...
Nonsmall cell lung cancer (NSCLC) with SMARCA4 deficiency represents a rare subset of lung tumors characterized by early metastasis, poor response to chemotherapy, and unfavorable prognosis. Established therapy strategies for SMARCA4-deficient NSCLC remain elusive. While immune checkpoint inhibitors have been proposed as a potential solution, their efficacy remains uncertain. Clinical factors such as tumor mutational burden (TMB), microsatellite instability, comutations, and programmed death-ligand 1 (PD-L1) expression may influence the treatment response of SMARCA4-deficient NSCLC. Additionally, PD-L1 expression on circulating tumor cells (CTCs) provides novel insights for monitoring, and its utility in SMARCA4-deficient NSCLC remains unexplored. The present report describes the case of a 71-year-old man diagnosed with SMARCA4-deficient NSCLC who had a history of heavy smoking and chronic cough. Imaging examination revealed metastatic lymph nodes. All serum tumor markers were elevated above the normal range. Histopathological and immunohistochemical analyses of the biopsy specimen from a primary lesion in the right upper lung demonstrated irregularly arranged tumor cells, SMARCA4 deficiency, and positive PD-L1 expression. Further next-generation sequencing confirmed SMARCA4 mutation, high TMB, and microsatellite stability (MSS). The patient received pembrolizumab treatment and experienced a sustained benefit for >40 months, with persistent PD-L1 expression on CTCs observed throughout the treatment. It was revealed that pembrolizumab therapy shows promise for patients with SMARCA4-deficient NSCLC with positive PD-L1 expression, high TMB, and MSS. Dynamic monitoring of PD-L1 status on CTCs may facilitate the assessment of the immunotherapy response, and the sustained positive PD-L1 expression on CTCs may imply continued benefit from immunotherapy for patients with SMARCA4-deficient NSCLC.
Serum heat shock protein family A member 9 protein as a biomarker for bortezomib resistance and poor prognosis in patients with multiple myeloma.
Chen L, Gao S, Lin L … +4 more , Liu S, Ma J, Zhang Z, Li Q
Anticancer Drugs · 2026 Feb · PMID 40916774 · Full text
Bortezomib resistance in multiple myeloma (MM) is a significant clinical challenge that limits the long-term effectiveness. Currently, there is a lack of reliable biomarkers to predict bortezomib resistance. Previous stu...
Bortezomib resistance in multiple myeloma (MM) is a significant clinical challenge that limits the long-term effectiveness. Currently, there is a lack of reliable biomarkers to predict bortezomib resistance. Previous studies reported that several proteins regulate bortezomib resistance through targeting ubiquitin-proteasome pathways, including heat shock protein family A member 9 (HSPA9), dickkopf Wnt signaling pathway inhibitor 1 (DKK1), proteasome 26S subunit non-ATPase 14 (PSMD14), and tripartite motif containing 21 (TRIM21). In our study, we aimed to analyze the expression of these proteins in MM patients and evaluate their potential as biomarkers for bortezomib resistance. Our study enrolled 46 newly diagnosed MM patients (38 bortezomib-sensitive and eight bortezomib-resistant patients) and 52 healthy controls, and serum samples were collected from the patients before initial treatments. The levels of HSPA9, DKK1, PSMD14, and TRIM21 proteins in serum samples were measured using ELISA. The diagnostic power of HSPA9 protein for bortezomib resistance was evaluated through receiver operating characteristic curves combined with the area under curve (AUC). The correlation between HSPA9 protein and clinicopathological features was examined using the chi-square test, and Kaplan-Meier method and Cox regression analysis were applied to assess prognostic value. Compared with healthy controls, increased HSPA9 and DKK1, but decreased TRIM21 protein expression, were observed in serum samples from MM patients. There was no statistical difference in PSMD14 protein expression between the two groups. Notably, compared with bortezomib-sensitive patients, only HSPA9 protein was found to be upregulated in bortezomib-resistant patients, whereas no differences were found in the other proteins. Furthermore, the AUC of serum HSPA9 for differentiating MM patients from healthy controls was 0.906 [95% confidence interval (CI): 0.843-0.968]. And serum HSPA9 expression could effectively differentiate bortezomib-resistant MM patients from bortezomib-sensitive MM patients, with an AUC of 0.845 (95% CI: 0.734-0.957). In addition, elevated serum HSPA9 expression positively correlated with advanced International Staging System stage, increased β2-MG, abnormal immunoglobulin, and bortezomib resistance. Higher serum HSPA9 was linked to shorter overall survival rate and independently predicted poor prognosis. Our study demonstrated that elevated serum HSPA9 protein serves as a potential biomarker for bortezomib resistance and poor prognosis in MM patients.
Identification of uridine phosphatase 1 as a potential therapeutic target in gastric cancer by integrated bioinformatics analysis and experimental validation.
Wang Y, Feng Y, Zhu C … +6 more , Guan L, Wang S, Zou A, Yu M, Yuan Y, Cai H
Anticancer Drugs · 2026 Mar · PMID 40855937 · Publisher ↗
Gastric cancer remains a major global health challenge, and its early diagnosis and prognosis prediction pose significant challenges to the current clinical treatment of gastric cancer. Finding gastric cancer biomarkers...
Gastric cancer remains a major global health challenge, and its early diagnosis and prognosis prediction pose significant challenges to the current clinical treatment of gastric cancer. Finding gastric cancer biomarkers is essential to comprehending its pathophysiology and creating novel targeted treatments. Following the acquisition and processing of the gastric cancer sample, the single-cell RNA sequencing data, monocyte subpopulation characterization, and cell type identification were performed. Key gene modules linked to gastric-cancer-related monocytes were identified using high-dimensional weighted gene co-expression network analysis. Machine-learning diagnostic models were created utilizing the discovered gastric-cancer-related monocyte-related genes (GCRMORGs). A prognostic model was developed with the uridine phosphatase 1 ( UPP1 )-related risk scores and verified in separate cohorts, and multiple immunological analyses were performed. Finally, using various experimental assays, we thoroughly investigated the function of the UPP1 gene in gastric cancer. Gastric cancer samples showed a distinct immune milieu topography with an abundance of monocytes. Eventually, 32 GCRMORGs were identified. Diagnostic models demonstrated a high degree of efficacy in differentiating between patients with gastric cancer and the control group. The prognostic model showed significant predictive value for gastric cancer patients' survival. At the same time, we have confirmed from experimental perspectives that a poor prognosis for patients is indicated by a high expression of UPP1 in gastric cancer tissue. Important monocyte subpopulations associated with gastric cancer samples were detected in our investigation. The prognosis of patients with gastric cancer can be predicted using a predictive model based on 32 GCRMORGs. In addition, focusing on UPP1 in gastric cancer may yield novel therapeutic targets and approaches.
Applying next-generation sequencing to predict short progression-free survival in patients with advanced EGFR -mutant lung adenocarcinoma receiving epidermal growth factor receptor tyrosine kinase inhibitors.
Lee PH, Hsiao YC, Huang YH … +5 more , Hsu KH, Tseng JS, Lin H, Chang GC, Yang TY
Anticancer Drugs · 2025 Nov · PMID 40773366 · Publisher ↗
For patients with advanced EGFR -mutant lung adenocarcinoma, progression-free survival (PFS) is significantly improved by epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) medications. However, a subs...
For patients with advanced EGFR -mutant lung adenocarcinoma, progression-free survival (PFS) is significantly improved by epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) medications. However, a subset of patients still experiences early disease progression. In this study, we aimed to identify potential risk factors associated with shorter PFS through next-generation sequencing (NGS) analysis. This retrospective study included patients with advanced EGFR -mutant lung adenocarcinoma who received first-line EGFR-TKI treatment with upfront NGS. The genetic alterations included two types, mutations and copy number variations. Alterations involving EGFR downstream signaling pathways were classified as ' PIK3CA-AKT/RAS-RAF alterations'. Clinical and histopathological data were also collected and analyzed. We studied a total of 82 advanced lung cancer patients with sensitive EGFR mutations. Multivariable analyses showed associations with a shorter PFS for the following factors: P IK3CA-AKT/RAS-RAF alterations [hazard ratio (HR) 3.197, P = 0.006], age ≤50 (HR 3.034, P = 0.010), and PD-L1 ≥50% (HR 2.256, P = 0.035). Based on the above risk factors, patients were classified into no-risk and ≥1 risk groups. In the no-risk group, third-generation EGFR-TKIs showed a numerically longer PFS compared to first/second-generation EGFR-TKIs (not reached vs. 20.0 months, P = 0.084). However, in patients with ≥1 risk factor, third-generation EGFR-TKIs showed no PFS advantages (6.6 vs. 6.2 months, P = 0.831). In conclusion, besides clinicopathological factors, NGS provides additional insights to predict shorter PFS after EGFR-TKI treatment. We identified three risk factors: (1) PIK3CA-AKT/RAS-RAF alterations, (2) age ≤50, and (3) PD-L1 ≥50%. Patients with these factors had poor PFS regardless of EGFR-TKI generation.
Patient-derived organoid modeling predicts personalized drug responses in prostate-metastatic mantle cell lymphoma: a case report.
Wang X, Fu G, Wan J … +6 more , Lin D, Shui M, Zhou T, Zhu S, Jiang P, Feng N
Anticancer Drugs · 2025 Nov · PMID 40762074 · Publisher ↗
Tumor heterogeneity represents a significant challenge in cancer treatment. Current therapeutic strategies frequently rely on single biopsy assessments that may not fully capture tumor complexity. In this study, we devel...
Tumor heterogeneity represents a significant challenge in cancer treatment. Current therapeutic strategies frequently rely on single biopsy assessments that may not fully capture tumor complexity. In this study, we developed prostate patient-derived organoids (PDOs) from a mantle cell lymphoma (MCL) case with prostatic metastasis. Monotherapy experiments revealed that the prostate organoids were sensitive to gemcitabine but resistant to rituximab and oxaliplatin. In combination therapy experiments, the half maximal inhibitory concentration value of gemcitabine increased, indicating that the combination regimen may attenuate its efficacy. In addition, the expression of prostate cancer markers prostate-specific membrane antigen and ETS-related gene was detected in the organoids. The research findings indicate that the PDO model not only dynamically monitors changes in drug sensitivity caused by heterogeneity but also serves as a powerful tool for predicting drug responses and optimizing precision treatment strategies. This is particularly applicable to clinical decision-making for highly heterogeneous tumors like MCL.
Inhibition of nuclear receptor coactivator 5 overcomes acquired lenvatinib resistance driven by protein kinase B-mammalian target of rapamycin signaling in hepatocellular carcinoma.
Zhou H, Zhang Q, Yang L … +9 more , Pan Z, Zheng H, Zhang Z, Li D, Li G, Liu X, Bao X, Liu C, Zhang W
Anticancer Drugs · 2025 Nov · PMID 40747694 · Full text
Lenvatinib, a multiple-receptor tyrosine kinase inhibitor, has gained recent approval for its use as a first-line treatment of hepatocellular carcinoma (HCC). While lenvatinib demonstrates notable therapeutic efficacy, t...
Lenvatinib, a multiple-receptor tyrosine kinase inhibitor, has gained recent approval for its use as a first-line treatment of hepatocellular carcinoma (HCC). While lenvatinib demonstrates notable therapeutic efficacy, the drug resistance undermines its sustained tumor control potential. The restricted clinical utility of lenvatinib underscores the imperative necessity to elucidate the mechanisms underpinning drug resistance. We established lenvatinib-resistant cell lines and investigated the changes in their biological characteristics. Next-generation sequencing was performed to identify genes associated with lenvatinib resistance. Western blots were utilized to confirm the involvement of these genes. Using lentiviral technology, we generated cell lines with lowered nuclear receptor coactivator 5 (NCOA5), a pivotal drug resistance-related gene, to explore the underlying resistance mechanism. Moreover, we developed a subcutaneous HCC xenograft tumor model to explore strategies for reversing drug resistance. Our study showed that HCC cells acquire resistance to lenvatinib through the activation of NCOA5, thereby stimulating the NCOA5-Protein Kinase B-mammalian target of rapamycin (AKT-mTOR) axis. Furthermore, the clinical evaluation of HCC specimens established a correlation between the activation of the NCOA5 pathway and the response to lenvatinib treatment. Everolimus, an mTOR inhibitor, in combination with lenvatinib and everolimus, exerted significant synergistic effects against HCC in vivo and in vitro . HCC cells develop resistance to lenvatinib by activating the NCOA5-AKT-mTOR pathway. The combination therapy of lenvatinib with everolimus is a promising strategy to overcome acquired resistance, thereby enhancing the clinical efficacy of lenvatinib.
E26 transformation-specific transcription factor 3 tips the balance: repressing tropomyosin 2 to fuel Yes-associated protein 1-driven cisplatin resistance in ovarian cancer.
Wang Y, Xu Z, He C … +4 more , Qu H, Yang Y, Lu Y, Dong X
Anticancer Drugs · 2025 Nov · PMID 40747607 · Publisher ↗
Cisplatin resistance remains a major challenge in the treatment of ovarian cancer, significantly limiting therapeutic efficacy. This study aimed to investigate the role of E26 transformation-specific transcription factor...
Cisplatin resistance remains a major challenge in the treatment of ovarian cancer, significantly limiting therapeutic efficacy. This study aimed to investigate the role of E26 transformation-specific transcription factor 3 (ELK3) in cisplatin resistance and elucidate the underlying molecular mechanism involving the tropomyosin 2 (TPM2)-Yes-associated protein 1 (YAP1) signaling axis. By silencing ELK3 and TPM2 in combination with cisplatin treatment, the regulatory effects of ELK3 and TPM2 on cisplatin sensitivity in ovarian cancer cells were evaluated. The interaction between ELK3 and the TPM2 promoter was verified via chromatin immunoprecipitation and dual-luciferase reporter assays. Western blotting was used to assess the expression of DNA damage marker gamma-histone H2AX and YAP1 to investigate the role of TPM2 in ELK3-mediated signaling and drug response. Cisplatin treatment markedly increased ELK3 expression. Knockdown of ELK3 enhanced cisplatin sensitivity by suppressing cell proliferation, promoting apoptosis, and increasing DNA damage. Mechanistically, ELK3 was directly bound to the promoter region of TPM2 and repressed its transcription. Downregulation of TPM2 subsequently led to increased activation of the YAP1 signaling pathway. Rescue experiments demonstrated that silencing TPM2 reversed the chemosensitizing effects of ELK3 knockdown. These findings highlight the ELK3/TPM2/YAP1 axis as a critical regulator of cisplatin resistance. By suppressing TPM2 and subsequently activating YAP1 signaling, our study identified ELK3 as a crucial transcriptional repressor that contributes to cisplatin resistance in ovarian cancer.
Safety and efficacy of ivosidenib in the treatment of isocitrate dehydrogenase 1 mutant cholangiocarcinoma and acute myeloid leukemia: a systematic review and meta-analysis.
Qasim R, Anmol L, Shakeel I … +6 more , Haseeb B, Bhatti HF, Iqbal U, Ahmad S, Hassan M, Raza M
Anticancer Drugs · 2025 Nov · PMID 40699201 · Publisher ↗
Isocitrate dehydrogenase 1 (IDH1) mutations have gained interest because of their association with malignancies, including cholangiocarcinoma and acute myeloid leukemia. Ivosidenib, an inhibitor of IDH1 mutations, inhibi...
Isocitrate dehydrogenase 1 (IDH1) mutations have gained interest because of their association with malignancies, including cholangiocarcinoma and acute myeloid leukemia. Ivosidenib, an inhibitor of IDH1 mutations, inhibits the formation of the oncometabolite D-2-HG, restoring normal cellular turnover and inhibiting tumorigenesis. In July 2024, a literature search was done using these databases: PubMed, Cochrane Library, and Embase. Studies were to show the safety and efficacy of ivosidenib using 95% confidence intervals (CIs). Preferred Reporting Items for Systematic reviews and Meta-Analyses flow guidelines were followed. Four articles involving 533 patients were included. The objective response rate (ORR) and progression-free survival (PFS) were significantly improved in the control group where risk ratio was 0.79, 95% CI: 0.71-0.89, Z = 4.05, a P value less than 0.001 for PFS, and odds ratio was 0.45, 95% CI: 0.30-0.68, Z value of 3.86, and P = 0.001 for ORR. The safety profile was favorable. Overall survival (OS) did not change significantly within the groups, as indicated by a P value of 0.78, risk ratio of 0.98, 95% CI: 0.83-1.15, and Z = 0.27. Ivosidenib demonstrated a PFS advantage and improved ORR with a favorable safety profile, but no effect on the OS. Evidence is suggestive of its plausibility for clinical usage as an adjunct therapy.
Effect of valproic acid and levetiracetam administration on the survival of glioma patients: a meta-analysis study.
Shirani A, Obeidinia M, Ziafati M … +3 more , Garavand J, Ramezani M, Ramezani F
Anticancer Drugs · 2025 Oct · PMID 40699178 · Publisher ↗
In this meta-analysis study, the effect of valproate (VPA) and levetiracetam (LEV) on the survival of glioma patients taking temozolomide (TMZ) was investigated. The cumulative hazard ratios (HR) of overall survival (OS)...
In this meta-analysis study, the effect of valproate (VPA) and levetiracetam (LEV) on the survival of glioma patients taking temozolomide (TMZ) was investigated. The cumulative hazard ratios (HR) of overall survival (OS) and progression-free survival from published clinical studies were determined using a random effects model to estimate the strength of the association between VPA/LEV and survival in glioma patients. The results showed that VPA (data from 2304 patients from 14 clinical trial studies) and LEV (data from 1610 patients from 11 clinical trial studies) increase OS by 20% [HR = 0.80; 95% confidence interval (CI), 0.69-0.94; P = 0.01] and 18% (HR = 0.82; 95% CI, 0.68-0.98; P = 0.03), respectively. Use of VPA and LEV as anticonvulsant drugs increased the OS of patients with glioma taking TMZ to an almost equal extent. These findings need to be confirmed in larger prospective studies.
VTCN1 emerges as a biomarker of immune tolerance in osimertinib-resistant lung cancer.
Wang L, Liu J, Shi B
Anticancer Drugs · 2025 Nov · PMID 40674089 · Publisher ↗
Osimertinib is an effective strategy for nonsmall-cell lung cancer (NSCLC). However, the acquired resistance neutralizes the efficacy of osimertinib. Herein, we investigated the potential biomarkers of osimertinib-resist...
Osimertinib is an effective strategy for nonsmall-cell lung cancer (NSCLC). However, the acquired resistance neutralizes the efficacy of osimertinib. Herein, we investigated the potential biomarkers of osimertinib-resistant lung cancer. GSE200894 was used to analyze the differentially expressed genes in osimertinib-resistant lung cancer. Sixty-two paired surgical specimens were collected from NSCLC patients with stage I-IV. Gene expression was detected using reverse transcription (RT)-qPCR, western blot, and immunohistochemistry. V-set domain containing T cell activation inhibitor 1 (VTCN1) was overexpressed in osimertinib-resistant lung cancer. High levels of VTCN1 predicted advanced stages and distant metastasis. Moreover, VTCN1 expression was negatively correlated with the purity of CD8+ T cells in lung cancer patients. VTCN1 inhibits the infiltration of effector-memory CD8+ T cells. In addition, overexpressed VTCN1 predicted the exhaustion of CD8+ T cells. VTCN1 inhibits the tumor-killing ability of CD8+ T cells. In summary, VTCN1 is overexpressed in osimertinib-resistant lung cancer patients. High levels of VTCN1 confer to inhibition of CD8+ T cell immunity and immune tolerance in osimertinib-resistant lung cancer patients.
Overcoming refractory leptomeningeal metastasis in nonsmall cell lung cancer with intrathecal pemetrexed and osimertinib: a case report.
Xue L, Zhao X, Tai X … +3 more , Zhang X, Zhang L, Li H
Anticancer Drugs · 2025 Oct · PMID 40663104 · Publisher ↗
Leptomeningeal metastasis (LM), a devastating complication of advanced nonsmall cell lung cancer (NSCLC), severely compromises patient survival and quality of life. Currently, standardized diagnostic criteria and treatme...
Leptomeningeal metastasis (LM), a devastating complication of advanced nonsmall cell lung cancer (NSCLC), severely compromises patient survival and quality of life. Currently, standardized diagnostic criteria and treatment protocols for NSCLC-associated LM remain undefined, posing significant clinical challenges. Here, we present a case of a 58-year-old female with advanced epidermal growth factor receptor (EGFR)-mutated (exon 19 deletion) lung adenocarcinoma who developed LM after failing first-line gefitinib therapy. Initial treatment with osimertinib (80 mg/day), a third-generation EGFR-tyrosine kinase inhibitor (TKI), achieved 8 months of disease control before LM progression. Cerebrospinal fluid genomic analysis revealed acquired EGFR mutations (exon19 L747-A750delins and exon18 L718Q). Combination therapy with intrathecal pemetrexed and standard-dose osimertinib temporarily alleviated neurological symptoms. Upon disease recurrence after 6 months, therapeutic intensification through increased intrathecal pemetrexed frequency and high-dose osimertinib (160 mg/day) resulted in sustained neurological improvement and prolonged survival with manageable toxicity. This case demonstrates the potential of optimized intrathecal/systemic TKI combination strategies for EGFR-mutant NSCLC with LM, providing clinical insights for this therapeutic dilemma.
Distribution of side effects of anti-EGFR treatments in patients with metastatic colorectal cancer and evaluation of their relationship with survival.
Erciyestepe M, Aydin O, Dinc Sonusen S … +4 more , Ozturk AE, Celik E, Atci MM, Erturk K
Anticancer Drugs · 2026 Feb · PMID 40626459 · Publisher ↗
Many previous studies have investigated cetuximab and panitumumab's efficacy, safety, and side effects. Only a few studies have evaluated the relationship between toxicity and survival. Therefore, we conducted this study...
Many previous studies have investigated cetuximab and panitumumab's efficacy, safety, and side effects. Only a few studies have evaluated the relationship between toxicity and survival. Therefore, we conducted this study to examine the relationship between the side effects of anti-EGFR agents and survival in metastatic colorectal cancer patients. Our study is a single-center retrospective analysis of the medical records of 100 metastatic colorectal cancer patients between September 2014 and September 2023. Overall survival (OS) was found to be statistically significantly longer in patients who developed skin toxicity during anti-EGFR treatment (26.0 vs. 70.0 months) ( P < 0.001). Similarly, OS was significantly better in patients with hypomagnesemia ( P < 0.001) and constipation ( P < 0.001) side effects. In contrast, OS was significantly worse in patients with lung toxicity ( P = 0.016). Ocular side effects during anti-EGFR treatment did not affect OS statistically significantly ( P = 0.268). The median PFS of patients with skin toxicity with anti-EGFR agents and hypomagnesemia in first-line treatment was 22.0 months (19.4-24.5) and 21.0 months (18.2-23.8), respectively ( P = 0.002, P = 0.022). In the second line, the median PFS of patients with skin toxicity and patients with hypomagnesemia who received anti-EGFR therapy was 19.0 months (6.2-31.8) and 17.0 months (8.4-25.6), respectively ( P = 0.013, P = 0.037). In our study, it was found that skin toxicity and hypomagnesemia positively affected both OS and PFS. OS was longer in patients with constipation, and OS was shorter in patients with lung toxicity. We suggest that survival might be predicted by monitoring side effects of these therapeutics; therefore, studies with larger cohorts are required.
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