Current Cancer Drug Targets - Volume 25, Issue 7, 2025

Cholesterol has been shown to be a potential risk factor for the occurrence and progression of breast cancer. This study aimed to investigate the regulation of DHCR7 in cholesterol synthesis and its role in Hedgehog (Hh) signaling pathway activation, as well as its impact on the progression of triple-negative breast cancer (TNBC).

We analyzed the gene expression data from the GSE76275 data set by bioinformatics analysis to determine the expression of cholesterol-related genes in TNBC. In the TNBC cell lines, including BT-549 and MDA-MB-231, RNA interference gene knockout was used to evaluate the functional impact of DHCR7. In addition, the SMO mutant (SMO^V329F) with anti-cholesterol binding inhibition was introduced to determine its interaction with the pathway changes mediated by DHCR7. Cell proliferation, migration, and signaling pathway activation were assessed through Western blotting, CCK-8 assay, transwell migration assay, and qPCR.

DHCR7 expression was significantly elevated in TNBC tissues and cell lines, enhancing the Hh pathway activity through cholesterol modulation. Knocking down DHCR7 and the SMO^V329F mutation both reduced the expression of Hedgehog-related proteins and inhibited cell proliferation and migration abilities. However, the SMO^V329F mutation reversed the inhibitory effect of knocking down DHCR7 on TNBC cells.

DHCR7 activates the Hedgehog pathway by regulating cholesterol to promote the development of TNBC. These findings provide insights into the regulatory roles of DHCR7 in cholesterol-related pathways and Hh signaling in TNBC cells, offering potential therapeutic targets for TNBC treatment.

The cardiotoxicity and subsequent Heart Failure (HF) induced by Doxorubicin (DOX) limit the clinical application of DOX. Valsartan (Val) is an angiotensin II receptor blocker that could attenuate the HF induced by DOX. However, the underlying mechanism of Val in this process is not fully understood.

In this study, we explored the cardio-protective mechanism of Val against DOX-induced cardiotoxicity using label-free ubiquitin-proteomic analysis.

Results showed that 27 lysine-ubiquitination sites in 25 proteins were differentially expressed between DOX and DOX+Val treated groups. In addition, the levels of ubiquitin modification of the myosin family and Ankrd1 were upregulated post-Val. Val also increased ATP production and activated the Akt/mTOR pathway by regulating the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) and cardiomyocyte calcium hemostasis.

The results highlight the value of label-free ubiquitin-proteomic analysis in defining the molecular mechanism of Val against HF and may be helpful in the development of new therapeutic agents for HF via targeting molecules defined in this research.

Transcription factor 19 (TCF19) is considered a crucial transcription factor and acts as an oncogene in a few cancers. Nevertheless, the effect and mechanism of TCF19 on glioma remain unknown.

This research aimed to explore the function of TCF19 on glioma progression and clarify the potential mechanism.

TCF19 and DHX32 expressions in glioma were determined using bioinformatics, Quantitative real-time PCR, and immunohistochemistry. MTT assay was carried out to detect the biological function of TCF19 and DHX32 in glioma cell multiplication. Cell-cycle distribution and apoptosis were measured by using FACS. The function of TCF19 on glioma growth was examined using tumor xenografts assay. Bioinformatics analysis, ChIP-qRT-PCR, and reporter gene assay were employed to illustrate the TCF19 target regulating DHX32 transcription.

TCF19 was observably upregulated in glioma and has important clinical significance. Overexpressing TCF19 expedited glioma cell multiplication and cell-cycle transition, meanwhile preventing apoptosis. TCF19 knockdown inhibited cell proliferation, cell-cycle transition, and tumour growth, simultaneously accelerating apoptosis. TCF19 expressions had a positive correlation with DHX32 expressions in glioma. It was demonstrated that TCF19 activated DHX32 transcriptional activity in glioma by combining it with the promoter of DHX32. DHX32 promoted glioma cell growth and cell-cycle transition while restraining apoptosis. Overexpressing DHX32 eliminated the function of TCF19 knockdown on cell multiplication, cell-cycle transition, and apoptosis. Moreover, TCF19 activated the β-catenin pathway by enhancing DHX32 transcriptional activity.

TCF19 promotes glioma cell multiplication and cell-cycle transition while suppressing apoptosis by modulating the β-catenin signaling pathway via accelerating DHX32 transcription. These findings provide a promising therapeutic target for glioma.

Non-small cell lung cancer (NSCLC) predominantly affects older adults; these patients have significant comorbidities, making them unsuitable for chemotherapy. This study aimed to evaluate the efficacy and safety of immune checkpoint inhibitor (ICI) along with anlotinib combination therapy as a first-line treatment in older NSCLC patients with programmed death ligand-1(PD-L1) expression<50%.

We conducted a retrospective observational study including 73 patients with advanced NSCLC treated at Nanjing Brain Hospital. All patients were aged 75 years or older and received first-line systemic therapy with a combination of PD-1 inhibitors and anlotinib. Clinical data were obtained from electronic medical records and analyzed through Kaplan-Meier estimates and Cox proportional hazards models to assess progression-free survival (PFS), overall survival (OS), and the influence of different variables.

The patients had a median age of 80 years. The median PFS was 9.8 months (95% CI: 7.9-11.7), and the median OS was 19.5 months (95% CI: 17.3-21.7). PD-L1 tumor proportion score (TPS) <1% (χ2=10.263, P=0.001) and absence of treatment-induced hypertension (χ2=12.804, P<0.001) were identified as independent risk factors for poor PFS. Advanced disease stage (χ2=11.900, P=0.001), PD-L1 TPS <1% (χ2=6.643, P=0.010), and having two or more chronic comorbidities (χ2=9.011, P=0.003) were independent risk factors for poor OS. Treatment-related hypertension was observed in 25% of patients and was associated with better PFS.

ICI-anlotinib combination therapy showed promising efficacy and an acceptable safety profile in older NSCLC patients. Future studies involving larger populations are necessary to validate these findings and determine the potential of PD-L1 levels as a biomarker for treatment stratification.

The Chinese chaste tree Vitexnegundo (VN) is a popular herb in South and Southeast Asia that has several health benefits, including the ability to inhibit tumor growth and induce apoptosis in multiple tumors. Literature revealed scanty research on breast cancer, with little focus on the molecular mechanism of the disease and an emphasis on targets, biological networks, and active components. Exploring natural compounds as possible therapeutic options is an old but still promising approach for drug discovery and development. This study used a thorough computational and statistical method to screen potential drug candidates.

The active ingredients and targets of VN were identified using SwissADME, SwissTargetPrediction, STITCH, IMPPAT database, KNapSAcK database, and literature. The OMIM and GeneCards databases were searched for possible targets related to breast cancer. The PASS online server was used to check the probability of active metabolite (Pa) against breast cancer. To build protein-protein interactions (PPI) networking, the intersection of disease and drug targets was uploaded to the STITCH database. Cytoscape software was used to analyze the topology parameters of networking to identify hub targets. Gene Ontology (GO) was analyzed using Metascape and ShinyGO, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis was performed using the David database and SR plot, and the site of expression and protein domain were studied using FunRich. We employed AutoDockvina, Discovery Studio, and UCSF ChimeraX software and auxiliary tools for molecular docking and analysis. Zincpharmer was used for pharmacophore mapping. ADMET analysis was conducted using ADMETsar, Swiss ADME, ADMETLab servers, and mypresto using GROMACS for molecular dynamics simulation (MDS).

A total of 65 targets and 21 active ingredients were identified. Further investigation was conducted on 20 hub targets selected through PPI networking construction. The enrichment analysis results indicated that the key factors were P, amyloid-beta response, cellular response to amyloid-beta, Pos. reg. of G2/M transition of the mitotic cell cycle, and response to a toxic substance. The molecular docking, pharmacophore mapping, and MD simulation results indicated that apigenin, kaempferol, and luteolin positively interacted with CDK1 and CDK6 proteins.

This study is the first to use network pharmacology, molecular docking, pharmacophore mapping, and MD simulation to identify the active ingredients, molecular targets, and critical biological pathways responsible for VN anti-breast cancer. The study provides a theoretical basis for further research in this area.

A retrospective analysis was carried out on data from advanced NSCLC patients who received either PD-1/L1 inhibitors combined with anlotinib or PD-1/L1 inhibitors combined with bevacizumab as second-line therapy. Clinical outcomes, including Overall Survival (OS), Progression-Free Survival (PFS), Objective Response Rate (ORR), Disease Control Rate (DCR), and Adverse Events (AEs), were compared between the two treatment groups.

The results revealed that patients receiving PD-1/L1 inhibitors combined with anlotinib exhibited better efficacy compared to patients receiving PD-1/L1 inhibitors combined with bevacizumab (mPFS 5.0m vs. 4.0m, mOS 10.0m vs. 8.0m, ORR 31.25% vs. 17.14%, DCR 65.63% vs. 45.71%). Additionally, both treatment regimens were generally well-tolerated, with most adverse events being manageable and of mild to moderate severity. However, compared with patients receiving PD-1/L1 inhibitors combined with bevacizumab, those receiving PD-1/L1 inhibitors combined with anlotinib have higher incidence rates of certain adverse reactions (hypertension: 34.38% vs. 17.14%, proteinuria: 25% vs. 14.29%), implying that drug combinations of the same treatment modality may exhibit differences in efficacy and adverse reactions.

In this comparative study, PD-1/L1 inhibitors combined with anlotinib demonstrated superior efficacy compared to PD-1/L1 inhibitors combined with bevacizumab as second-line therapy for advanced NSCLC patients, with a manageable safety profile. These findings provide valuable clinical evidence for guiding treatment decisions in this patient population.

Icotinib and almonertinib are efficacious for non-small cell lung cancer (NSCLC) factor patients with epidermal growth receptor (EGFR)-mutation. Patients who previously used EGFR tyrosine kinase inhibitor (EGFR TKI) may switch to another one due to the adverse events.

Here, we report a case of a 73-year-old male patient with advanced lung adenocarcinoma in which an EGFR (exon 21 L858R substitution) was found. Icotinib (125mg three times daily) was administered initially. He achieved partial response two months later but developed acute interstitial lung disease (grade 2) with dry cough and chest tightness five months later. Icotinib was discontinued, and treatment with methylprednisolone improved the interstitial lung disease. Chemotherapy with pemetrexed, carboplatin, and bevacizumab was initiated as subsequent therapy. Considering the effectiveness of EGFR-TKIs, we decided cautiously to rechallenge the third-generation TKI almonertinib administration. The patient successfully received almonertinib for almost one year without the recurrence of interstitial lung disease and tumor progression. ILD was an infrequent but often life-threatening reaction associated with icotinib.

This is the first reported case of successful switching from icotinib to another EGFR TKI because of interstitial lung disease associated with icotinib, suggesting that EGFR-TKIs rechallenge because of adverse events rather than progression might provide a significant benefit in patients with EGFR driver positive NSCLC.