Nanoparticle-Mediated Cosilencing of Drug Resistance and Compensatory Genes Enhances Lung Cancer Therapy

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Non-small cell lung cancer (NSCLC) is challenging to treat due acquired drug resistance, leading high mortality rates. NSCLC patients with mutations in the epidermal growth factor receptor (EGFR) region are treated tyrosine kinase inhibitors (TKI) as a first-line treatment, but many develop resistance within 1-2 years. AXL overexpression contributes over 25% of patients, shown by tumor analyses, prompting efforts small-molecule targeting AXL. However, we found that repression increases compensatory FN14 signaling could affect therapeutic efficacy. Therefore, chose evaluate efficacy after silencing both and genes using short interfering RNA (siRNA) therapy. While siRNAs more selective than inhibitors, they prone vivo degradation. To address this, developed gelatin nanoparticles carrying (GsiAF). These were designed protect siRNA from serum degradation allow antibody functionalization on their surface. We demonstrate GsiAF selectively effectively silences respective under vitro conditions, thereby overcoming signaling. Results indicate was successful delivering tumors downregulating genes. show coinhibition has decreased TKI cells significantly reduced mice bearing cancer. The gelatin-siRNA nanoconstruct combined represents promising strategy for other cancers, potential future clinical translation.

Language: Английский

---

Development of new anticancer thiadiazole-sulfonamides as dual EGFR/carbonic anhydrase inhibitors

Future Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 16

Published: May 8, 2025

Thiadiazole-sulfonamide derivatives were synthesized as dual inhibitors of epidermal growth factor receptor (EGFR) and carbonic anhydrase IX (CA-IX) to develop selective anticancer agents. Cytotoxicity was evaluated against MDA-MB-231 MCF-7 breast cancer cells, with selectivity tested on Vero cells. Enzymatic inhibition studies conducted EGFR CA-IX, using erlotinib acetazolamide reference drugs. Apoptosis assessed through gene expression analysis BAX/Bcl-2, caspase-8, caspase-9, alongside flow cytometry for apoptosis cell cycle analysis. Molecular docking 200 ns molecular dynamics (MD) simulations binding interactions. Density Functional Theory (DFT) calculations in silico ADMET predictions stability, electronic properties, safety. Compound 14 exhibited potent cytotoxicity (IC₅₀ = 5.78 μM, MDA-MB-231; 8.05 MCF-7) high 313.08 Vero). It inhibited 5.92 nM) CA-IX 63 nM), surpassing induction confirmed by a 13.97-fold increase caspase upregulation, G1-phase arrest. Computational analyses stable favorable represents promising EGFR/CA-IX inhibitor activity. Further vivo are warranted.

Language: Английский

---

Moving beyond traditional therapies: the role of nanomedicines in lung cancer

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 8, 2024

Amidst a global rise in lung cancer occurrences, conventional therapies continue to pose substantial side effects and possess notable toxicities while lacking specificity. Counteracting this, the incorporation of nanomedicines can notably enhance drug delivery at tumor sites, extend drug’s half-life mitigate inadvertent toxic adverse impacts on healthy tissues, substantially influencing cancer’s early detection targeted therapy. Numerous studies signal that nano-characteristics play pivotal role, further interplay with immune, photothermal, genetic factors exist. This review posits progression towards multimodal combination could potentially establish an efficacious platform for treatments. Current split into active passive targeting. Active focus single target, often unsatisfactory results. Yet, developing systems targeting multiple sites chart new paths Conversely, low rates limit therapies. Utilizing EPR effect bind specific ligands nanoparticles cell receptors might create regime combining active-passive targeting, elevating nanomedicines’ concentration target sites. collates recent advancements through lens nanomedicine’s attributes therapeutics, novel carrier classifications, therapeutic modalities their mechanisms, proposing emergence multi-target nanocomposite combined treatments will pioneer approaches tools future clinical

Language: Английский

---

Efficacy and Safety of Amivantamab in Advanced or Metastatic EGFR-Mutant Non-Small Cell Lung Cancer: A Systematic Review

Journal of Clinical Medicine, Journal Year: 2024, Volume and Issue: 13(18), P. 5489 - 5489

Published: Sept. 16, 2024

Objectives: This systematic review aimed to examine the efficacy and safety profile of amivantamab in patients with advanced or metastatic non-small cell lung cancer (NSCLC) EGFR mutations. Methods: Three scientific databases, PubMed, Cochrane library ClinicalTrials.gov were searched for relevant articles up until 30 June 2024. Progression-free survival (PFS), overall (OS), objective response rate (ORR) ≥3 grade adverse events (AE) outcomes interest. Results: Five clinical trials included this review, reporting data from 1124 (safety population; n = 1091 population), who received as a monotherapy combination other treatments, both first-line relapsed/refractory setting. The median PFS groups that ranged 4.3 8.3 months, while lowest observed OS was 10.2 months. ORR 30% 73%. 3 higher AEs 35% 92%, serious 29% 52%. Infusion-related reactions (IRRs) 42% 78% among intravenously, 13% IRR found group subcutaneously. Conclusions: Current evidence suggests is an effective treatment option NSCLC Amivantamab-based combinations may prolong naïve those have progressed on chemotherapy tyrosine kinase inhibitors.

Language: Английский

---

Deoxybouvardin targets EGFR, MET, and AKT signaling to suppress non-small cell lung cancer cells

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Sept. 6, 2024

Language: Английский

---

Integrating anoikis and ErbB signaling insights with machine learning and single-cell analysis for predicting prognosis and immune-targeted therapy outcomes in hepatocellular carcinoma

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 11, 2024

Background Hepatocellular carcinoma (HCC) poses a significant global health challenge due to its poor prognosis and limited therapeutic modalities. Anoikis ErbB signaling pathways are pivotal in cancer cell proliferation metastasis, but their relevance HCC remains insufficiently explored. Methods This study evaluates the prognostic significance of anoikis by utilizing data from The Cancer Genome Atlas (TCGA), International Consortium (ICGC), three additional independent validation cohorts, an in-house cohort. Advanced bioinformatics analyses 167 machine learning models based on leave-one-out cross-validation (LOOCV) were used predict assess outcomes immune-targeted therapies. Additionally, key biological processes further investigated. Results single sample Gene Set Enrichment Analysis revealed strong correlation between upregulated high anoikis-expressing tumors clinical outcomes. development Anoikis-ErbB Related Signature (AERS) using LASSO + RSF model demonstrated robust predictive capabilities, as validated across multiple patient proved effective predicting responses Further investigation highlighted activated NOTCH decreased macrophage infiltration was associated with resistance sorafenib immune checkpoint inhibitors, evidenced bulk single-cell RNA sequencing (scRNA-seq). Conclusion AERS provides novel tool for paves way approaches, underscoring potential integrated molecular profiling enhancing treatment strategies HCC.

Language: Английский

---

Investigating the Efficacy of EGFR-TKIs and Anti-VEGFR Combination in Advanced Non-Small Cell Lung Cancer: A Meta-Analysis

Cancers, Journal Year: 2024, Volume and Issue: 16(6), P. 1188 - 1188

Published: March 18, 2024

Introduction: The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in combination with anti-vascular endothelial (VEGFR) agents have shown improved survival outcomes recent studies. However, its efficacy related to as a first- or second-line agent and based on generations remains be explored. This study estimated the of EGFR-TKIs plus anti-VEGFR defined populations advanced non-small cell lung cancer (NSCLC) patients overall, second line treatment, different bevacizumab subgroup. Methods: A literature search was conducted using PubMed, SCOPUS, Cochrane Library, ClinicalTrials.gov databases through June 2023 identify primary research reporting NSCLC. Studies that were single-arm, published non-English languages, had missing data excluded. meta-analysis generate pooled hazard ratios (HRs) 95% confidence intervals (CI) for overall (OS) progression-free (PFS). Methodological quality risk bias studies assessed Handbook Systematic Reviews Interventions tool. Results: total 20 randomized controlled trials included qualitative synthesis, 11 (2182 participants) meta-analysis. Patients’ median age ranged from 58 68 years; 36% 70% female; most them IIIa/b IV stage cancer. In meta-analyses, resulted PFS (HR, 0.73; CI: 0.61, 0.86; p < 0.00001) NSCLC but no impact OS 0.93; 0.79, 1.10; = 0.41). first treatment first-generation also 0.64; 0.57, 0.71; 0.00001; HR, 0.63; 0.56, respectively, however, OS. Conclusions: Our indicated not only showed similar results compared EGFR-TKI alone.

Language: Английский

---

Strategies for enhancing non-small cell lung cancer treatment: Integrating Chinese herbal medicines with epidermal growth factor receptor-tyrosine kinase inhibitors therapy

European Journal of Pharmacology, Journal Year: 2024, Volume and Issue: 980, P. 176871 - 176871

Published: Aug. 6, 2024

Language: Английский

---

Deciphering the Dynamics of EGFR-TKI Resistance in Lung Cancer: Insights from Bibliometric Analysis

Drug Design Development and Therapy, Journal Year: 2024, Volume and Issue: Volume 18, P. 4327 - 4343

Published: Sept. 1, 2024

EGFR-TKI resistance poses a significant challenge in the treatment landscape of non-small cell lung cancer (NSCLC), prompting extensive research into mechanisms and therapeutic strategies. In this study, we conduct bibliometric analysis to elucidate evolving hotspots trends resistance, offering insights for clinical interventions scientific inquiries.

Language: Английский

---

Evaluation of the role of EGFR exon 19 747–750 deletion mutation and plasma amino acid profile in the development of lung cancer

Molecular Biology Reports, Journal Year: 2024, Volume and Issue: 51(1)

Published: Oct. 4, 2024

Language: Английский

---