Anti-Cancer Drugs最新文献

Uncommon atypical mutations account for 10-15% of all epidermal growth factor receptor (EGFR) activating mutations in nonsmall-cell lung cancer (NSCLC). Tumors harboring rare EGFR mutations show highly heterogeneous responses to EGFR tyrosine kinase inhibitors (TKIs). There is insufficient clinical evidence for uncommon types of EGFR mutations, especially those with compound EGFR mutations. In addition, for those with uncommon compound EGFR mutations, few studies have focused on acquired resistance mechanisms and subsequent treatment strategies after disease progression on EGFR-TKIs. Here, a 66-year-old smoking male was diagnosed with lung adenocarcinoma accompanied by pleural metastasis. A rare L833V/H835L compound mutation in exon 21 of EGFR was detected in tumor biopsy by next-generation sequencing. Afatinib was used as first-line therapy and showed favorable efficacy. The patient continued afatinib treatment for a duration of 24 months. A new T790M mutation was detected with a rebiopsy after progression on afatinib. Then the patient received cryoablation therapy and a third-generation EGFR-TKI, furmonertinib. Our case suggests that a comprehensive screening for EGFR mutations should be conducted before and during treatment in clinical practice, and afatinib and furmonertinib could be first- and second-line treatment options in NSCLC patients harboring EGFR L833V/H835L mutations.

Micro-RNAs play essential roles in developing and progressing nonsmall cell lung cancer (NSCLC) and drug resistance. Nevertheless, the functions and mechanisms are partly explored. Therefore, the present study analyzes the effect of circ_0006528 and the mechanism of regulation of NSCLC cell progression by sponging miR-892a to regulate neuroblastoma rat sarcoma viral oncogene (NRAS) expression. Initially, circ_0006528 is identified using divergent primers-based PCR and RNase R exonuclease treatments. After administration of the designed circ_0006528-specific siRNA, the RT-qPCR analysis is used to determine the interference efficiency of siRNA. At the same time, cell growth, invasion, and migration are assessed by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT), Transwell, and scratch assays in the NSCLC cell lines [secretory pathway Ca2+-ATPase isoform 1 (SPCA-1) and A549] in vitro, respectively. Further, miR-892a inhibitor is added to the cells for functional recovery assay. Finally, the xenograft mouse model is constructed to explore the effect of circ_0006528 on tumor growth in vivo . The RT-qPCR analysis in 66 pairs of NSCLC cancer and noncancerous tissues revealed that circ_0006528 is highly expressed in NSCLC patient tissues. The RNase R experiments revealed that HSA_circ_0006528 is unaffected by RNase R exonuclease. MTT assay showed that knockdown of hsa_circ_0006528 by siRNA significantly decreased cell proliferation and viability in A549 and SPCA-1 cells. The luciferase reporter assay showed direct binding of hsa_circ_0006528 to miR-892a, and miR-892a targets binding NRAS. In addition, the miR-892a inhibitor terminated the hsa_circ_0006528 siRNA, triggering inhibition of proliferation, invasion, and migration of NSCLC cells. In summary, the study revealed that the knockout of hsa_circ_0006528 downregulation of NRAS expression by sponging miR-892a inhibited NSCLC cell growth and invasion.

The objective of this study is to assess the differential expression of ferroptosis suppressor protein 1 (FSP1) in relation to clinical features, platinum resistance, and recurrence in epithelial ovarian cancer (EOC). In addition, the potential significance of FSP1 in EOC as a predictor of platinum resistance and recurrence in EOC was explored. Patients with pathologically confirmed EOC who underwent surgical treatment were included in this analysis. Immunohistochemistry was employed to evaluate FSP1 expression in ovarian tissues, with quantitative analysis performed on the samples. Clinical data were collected during follow-up, and patients were categorized according to platinum resistance and recurrence criteria. Statistical analysis was conducted using SPSS version 27.0. A total of 40 tissue samples from patients with EOC were analyzed, along with 21 samples from benign ovarian tumors and 20 samples from normal ovarian tissues. The expression of FSP1 was significantly higher in the EOC group compared to both benign and normal tissue groups. Meanwhile, the expressions of FSP1 were higher in groups with clinically advanced stages, high-grade carcinoma, presence of cancerous ascites, lymph node metastasis, and in the clear cell EOC group, compared to those with clinically early stages, low-grade carcinoma, absence of cancerous ascites, no lymph node metastasis, and other pathological subtypes. A positive linear correlation was identified between FSP1 expression in EOC tissues and serum levels of CA125 and human epididymis protein 4 at the time of diagnosis. The elevated expression of FSP1 is positively correlated with serum CA125 and human epididymis protein 4 levels at the time of diagnosis, which is a risk factor for EOC drug resistance and recurrence. These findings suggest that FSP1 may serve as a valuable biomarker for predicting platinum resistance and recurrence in patients with EOC.

The uncertain ferroptosis-related role of berberine in prostate cancer was explored using network pharmacology methodology. Integration of ferroptosis targets in prostate cancer from the Genecard database and berberine targets from the Traditional Chinese Medicine Systems Pharmacology and SwissTargetPrediction databases revealed 17 common targets. Among these, 10 hub genes, including CCNB1 , CDK1 , AURKA , AR , CDC42 , ICAM1 , TYMS , NTRK1 , PTGS 2, and SCD , were identified. Enrichment analyses yielded 799 Gene Ontology terms and 23 Kyoto Encyclopedia of Genes and Genomes pathways associated with berberine-related targets. Molecular docking simulations indicated berberine's binding capacity to all hub genes. In-vitro studies on LNCaP and PC3 cells demonstrated berberine's inhibition of cell proliferation and significant downregulation of TYMS , CCNB1 , AURKA , CDK1 , and SCD in both cell lines. Berberine exhibited cell line-specific effects by reducing AR expression in LNCaP cells and suppressing ICAM1 in PC3 cells. Overall, berberine shows promise in inhibiting prostate cancer progression through modulation of ferroptosis-related genes, including TYMS , AR , CCNB1 , AURKA , CDK1 , ICAM1 , NTRK1 , SCD , and CDC42 .

This study aimed to evaluate the efficacy of pyrotinib, an orally administered small molecule tyrosine kinase inhibitor, combined with neoadjuvant chemotherapy in treating patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Pyrotinib works by inhibiting the HER2 signaling pathway, thereby preventing tumor cell growth. This single-arm clinical trial aimed to assess the total pathological complete response (tpCR; ypT0/is and ypN0) rate as the primary endpoint. A total of 27 patients were enrolled, each receiving 4-8 cycles of pyrotinib in combination with neoadjuvant chemotherapy. Pyrotinib combined with neoadjuvant chemotherapy demonstrated notable antitumor activity in patients with HER2-positive breast cancer. Among 26 patients, the tpCR rate was 26% (7/26), while the breast pathological complete response rate was 30% (8/26), indicating complete inhibition of the primary tumor in some cases. Notably, patients with HR-negative breast cancer demonstrated a higher tpCR rate compared with those with HR-positive breast cancer. The treatment regimen was well-tolerated. Diarrhea was the most common adverse event, occurring in 92.3% of patients, with 46.2% experiencing grade 3 or higher diarrhea. No severe adverse events or treatment-related fatalities were reported.

Small cell lung cancer (SCLC) is a highly aggressive form of lung cancer with limited therapeutic options and poor prognosis. In this study, we explored the therapeutic potential of BGJ398, a selective fibroblast growth factor receptor (FGFR) inhibitor, alone and in combination with standard chemotherapy (cisplatin and paclitaxel) in SCLC. High-throughput screening of kinase inhibitors was performed on three SCLC cell lines (NCI-H446, NCI-H69, and NCI-H182), identifying BGJ398 as one of the most potent and selective inhibitors. BGJ398 demonstrated significant synergy with cisplatin and paclitaxel in vitro , as indicated by combination index values below 1. In vivo , combination treatments significantly inhibited tumor growth and extended survival in SCLC xenograft models compared to monotherapies. Notably, the combination of BGJ398 with cisplatin exhibited the most pronounced tumor suppression and survival benefits. Immunohistochemistry analysis confirmed that BGJ398 effectively inhibited FGFR signaling pathways, reducing levels of phosphorylated FGFR, protein kinase B, signal transducer and activator of transcription 3, and extracellular signal-regulated kinase. These findings suggest that BGJ398, particularly in combination with chemotherapy, holds significant promise as a treatment strategy for SCLC, providing enhanced anti-tumor efficacy and improved survival outcomes.

Recent studies have shown that Janus Kinase inhibitors can enhance the tumor therapeutic effect of immune checkpoint inhibitors. However, it remains to be studied whether TYK2 selective inhibitors can enhance the therapeutic effect of small molecule PD-L1 inhibitors in triple-negative breast cancer (TNBC). We verified the efficacy of the combination of the selective TYK2 inhibitor Deucravacitinib and the small molecule inhibitor of PD-L1, INCB086550, in two TNBC animal models: a syngeneic mouse model (4T1 with humanized PD-L1) and a peripheral blood mononuclear cell (PBMC)-humanized model (MDA-MB-231). Following that, we explored the regulation of immune cell activity in tumors by the combined treatment using flow cytometry. Finally, we validated the expression of genes related to the regulated immune cells through reverse transcription-PCR. Both animal models demonstrated that the addition of a TYK2 inhibitor to a PD-L1 inhibitor significantly enhanced the antitumor capabilities of mice with good safety profiles. The combined therapy significantly elevated the counts of T, B, and natural killer cells while concurrently diminishing myeloid-derived suppressor cells in the syngeneic model. Similarly, in the PBMC-humanized model, this therapy markedly augmented progenitor-like and proliferative precursor-like CD8 T cells, while effectively diminishing exhausted and terminally differentiated CD8 T cell populations. This enhanced antitumor effect is associated with the modulation of antitumor immune-related gene expression by the combined therapy. The combination of TYK2 inhibitors and immune checkpoint inhibitors is a potentially effective strategy for treating TNBC.

We aimed to explore the role of ikarugamycin (IKA) in breast cancer, its connection with hexokinase-2 (HK-2) repression, and tissue factor (TF). This study sought to extend the role of HK-2 as a TF activator in a comprehensive analysis of these interactions from the enzyme, gene, and protein levels. The investigation was performed with MDA-MB-231 and MCF-7 breast cancer lines. The oxidative stress index (OSI), lactate production, and HK activity were assessed using colorimetric assays. Western blot and quantitative PCR analyses were performed to determine HK-2 and TF expressions. Prothrombin time Tests additionally assessed the effect of IKA therapy on TF activation. Three over four significantly downregulated genes were identified after a specific analysis of the IKA's effect on HK-2 and TF in breast cancer cell lines. In the IKA treatment group, lactate production was markedly reduced ( P  < 0.05) and hexokinase activity was found to be reduced in all groups ( P  < 0.05, <0.01). Paclitaxel cytotoxicity independently causes lower OSI in all IKA-treated groups as compared to controls even though OSI is elevated in IKA groups compared to control. Molecular analysis results demonstrated significantly downregulated HK-2 and TF expressions at the protein level ( P  < 0.05, P  < 0.01). Partial thromboplastin time results also showed that IKA-treated cells had longer TF activation duration. A potential indirect association of HK-2 inhibition and TF regulation in breast cancer cells is put forward in this study by presenting IKA's bioactivation of breast cancer in all gene, protein, and enzyme levels.

In gastric cancer, the relationship between human epidermal growth factor receptor 2 (HER2), the cyclic GMP-AMP synthase-stimulator of the interferon genes (cGAS-STING) pathway, and autophagy remains unclear. This study examines whether HER2 regulates autophagy in gastric cancer cells via the cGAS-STING signaling pathway, influencing key processes such as cell proliferation and migration. Understanding this relationship could uncover new molecular targets for diagnosis and treatment. Through lentiviral transfection, cell counting kit-8 assays, colony formation, transwell migration, scratch assays, and siRNA, we found that HER2 overexpression suppresses the cGAS-STING pathway, inhibits autophagy, and enhances the migratory ability of gastric cancer cells. In contrast, HER2 knockdown activates the cGAS-STING pathway, promotes autophagy, and reduces cell migration. We further observed that the inhibition of autophagy using chloroquine (CQ) increases the migration ability of HER2-overexpressing cells. Moreover, interfering with STING expression reversed the migration defects caused by HER2 knockdown, underscoring the critical role of the cGAS-STING pathway in HER2-regulated cell migration. We also revealed that high STING expression in gastric cancer is significantly associated with poor prognosis. STING expression was identified as an independent prognostic factor for survival (hazard ratio, 1.942; 95% confidence interval, 1.06-3.54; P  = 0.031). These results highlight the importance of HER2-driven regulation of autophagy through the cGAS-STING pathway in gastric cancer progression and its potential as a therapeutic target.

A predictive model for long-term survival is needed, and mitochondrial dysfunction is a key feature of cancer metabolism, though its link to glioma is not well understood. The aim of this study was to identify the molecular characteristics associated with glioma prognosis and explore its potential function. We analyzed RNA-seq data from The Cancer Genome Atlas and identified differentially expressed mitochondrial long noncoding RNAs (lncRNAs) using R's 'limma' package. A prognostic model was developed using 10 selected lncRNAs and validated with Cox regression and least absolute shrinkage and selection operator algorithm. The model's efficacy was assessed using Kaplan-Meier and receiver operating characteristic curve analyses, and its correlation with immune cell profiles and drug sensitivity was explored. A 10-mitochondria-related LncRNA signature was generated. The median risk score values are used to classify glioma samples into low-risk and high-risk groups. In breast patients, the signature-based risk score demonstrated a more potent ability to predict survival than conventional clinicopathological features. Furthermore, we noted a substantial disparity in the number of immune cells, including B cells, CD8 + T cells, and macrophages, between the two groups. In addition, the high-risk group exhibited lower half-maximal inhibitory concentration values for specific chemotherapy medications, including bortezomib, luminespib, rapamycin, and 5-fluorouracil. Our study elucidates the diagnostic and prognostic value of mitochondria-related-lncRNAs in the promotion, suppression, and treatment of glioma.