Examination of the Functional Relationship between PD-L1 DNA Methylation and mRNA Expression in Non-Small-Cell Lung Cancer DOI Open Access
Tina Vilsbøll,

Nina Dybdal,

Tina Fuglsang Daugaard

et al.

Cancers, Journal Year: 2023, Volume and Issue: 15(6), P. 1909 - 1909

Published: March 22, 2023

Immunotherapy targeting the interaction between programmed cell death protein 1 (PD-1) and death-ligand (PD-L1) is a treatment option for patients with non-small-cell lung cancer (NSCLC). The expression of PD-L1 by NSCLC cells determines effectiveness, but relationship DNA methylation has not been clearly described. We investigated methylation, mRNA expression, in lines tumor biopsies. used clustered regularly interspaced short palindromic repeats-associated 9 (CRISPR-Cas9) to modify genetic contexts endonuclease deficient Cas9 (dCas9) fusions ten-eleven translocation methylcytosine dioxygenase (TET1) (cytosine-5)-methyltransferase 3A (DNMT3A) manipulate methylation. In lines, we identified specific CpG sites levels inversely correlated expression. However, inducing interferon-γ did decrease level these sites, using CRISPR-Cas9, found that directly confer negative regulation. dCas9-TET1 dCas9-DNMT3A could induce hypo- hyper-methylation, respectively, latter conferring showing functional impact biopsies, inverse correlation was weak. conclude there regulatory link since measures are weakly associated, this study highlights need further research before can be implemented as biomarker drug target improve effectiveness PD-1/PD-L1 immunotherapy NSCLC.

Language: Английский

In-silico identification and exploration of small molecule coumarin-1,2,3-triazole hybrids as potential EGFR inhibitors for targeting lung cancer DOI
Sunil Kumar, Iqra Ali, Faheem Abbas

et al.

Molecular Diversity, Journal Year: 2024, Volume and Issue: unknown

Published: March 12, 2024

Language: Английский

Citations

5
Emerging paradigms and recent progress in targeting ErbB in cancers DOI Creative Commons

Nicolas Stoup,

Maxime Liberelle, Nicolas Lebègue

et al.

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(6), P. 552 - 576

Published: May 25, 2024

The epidermal growth factor receptor (EGFR) family is a class of transmembrane proteins, highly regarded as anticancer targets due to their pivotal role in various malignancies. Standard cancer treatments targeting the ErbB receptors include tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Despite substantial survival benefits, achievement curative outcomes hindered by acquired resistance. Recent advancements anti-ErbB approaches, such inhibitory peptides, nanobodies, targeted-protein degradation strategies, bispecific (BsAbs), aim overcome More recently, emerging insights into cell surface interactome open new avenues for modulating signaling specific domains partners. Here, we review recent progress elucidate paradigms that underscore significance EGF domain-containing proteins (EDCPs) ErbB-targeting pathways.

Language: Английский

Citations

5
Derivation of a new model of lung adenocarcinoma using canine lung cancer organoids for translational research in pulmonary medicine DOI Creative Commons

Yomogi Shiota,

Mohamed Elbadawy, Kazuhiko Suzuki

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 165, P. 115079 - 115079

Published: July 4, 2023

Canine primary lung cancer (cPLC) is a rare malignant tumor in dogs, and exhibits poor prognosis. Effective therapeutic drugs against cPLC have not been established yet. Also, resembles human histopathological characteristics gene expression profiles thus could be an important research model for this disease. Three-dimensional organoid culture known to recapitulate the tissue dynamics vivo. We, therefore, tried generate organoids (cPLCO) analyzing of cPLC. After samples from corresponding normal were collected, cPLCO successfully generated, which recapitulated architecture cPLC, expressed adenocarcinoma marker (TTF1), exhibited tumorigenesis The sensitivity anti-cancer was different among strains. RNA-sequencing analysis showed significantly upregulated 11 genes compared with canine (cNLO). Moreover, enriched MEK-signaling pathway cNLO. MEK inhibitor, trametinib decreased viability several strains inhibited growth xenografts. Collectively, our might useful tool identifying novel biomarkers new dog cancer.

Language: Английский

Citations

12
Genome-wide CRISPR-Cas9 screening identifies ITGA8 responsible for abivertinib sensitivity in lung adenocarcinoma DOI

Xuan-guang Li,

Guangsheng Zhu, Pengfei Cao

et al.

Acta Pharmacologica Sinica, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 14, 2025

Language: Английский

Citations

0
Targeting the Tumor Microenvironment in EGFR-Mutant Lung Cancer: Opportunities and Challenges DOI Creative Commons
Jeong Uk Lim, Junyang Jung, Yeon Wook Kim

et al.

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 470 - 470

Published: Feb. 14, 2025

Tyrosine kinase inhibitors (TKIs) have transformed the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. However, resistance remains a major challenge in clinical practice. The tumor microenvironment (TME) is complex system composed cells, immune and non-immune non-cellular components. Evidence indicates that dynamic changes TME during TKI are associated with development resistance. Research has focused on identifying how each component interacts tumors TKIs to understand therapeutic targets could address In this review, we describe components, such as fibroblasts, blood vessels, checkpoint proteins, cytokines, interact EGFR-mutant they can promote TKIs. Furthermore, discuss potential strategies targeting novel approach.

Language: Английский

Citations

0
Transformation from acquired EGFR 19del/C797S to EGFR 19del/T790M in an advanced non-small cell lung cancer patient: a case report and literature review DOI Creative Commons
Xin Jin,

Yaping Quan,

Jiao Liu

et al.

Anti-Cancer Drugs, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 14, 2025

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the first-line treatment of choice for patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, treated these eventually develop resistance. One most common mechanisms is emergence EGFR C797S mutation. Whether first-generation (e.g. icotinib or gefitinib) can sustainably control EGFR-sensitive mutations/C797S NSCLC following third-generation inhibitor remains insufficiently reported. Our case report discusses a female patient adenocarcinoma carrying an exon 19 E746_A750delELREA mutation who received almonertinib as and developed resistance during therapy. The was subsequently double dose 8 months until disease progression occurred, along development 20 T790M point TP53 This provides clinical evidence suggesting that EGFR-TKIs may be effective strategy acquired 19del/C797S TKI

Language: Английский

Citations

0
CD105 blockade restores osimertinib sensitivity in drug-resistant EGFR-mutant non-small cell lung cancer DOI Creative Commons
Manish Thiruvalluvan, Sandrine Billet, Zhenqiu Liu

et al.

Drug Resistance Updates, Journal Year: 2025, Volume and Issue: 81, P. 101237 - 101237

Published: March 12, 2025

To investigate the role of CD105 in mediating drug resistance to EGFR-targeted therapy non-small cell lung cancer (NSCLC). Imaging mass cytometry was conducted on 66 NSCLC tumors, 44 which had EGFR mutations. We correlated clinical variables, including overall survival, with (endoglin) expression, a co-receptor for bone morphogenetic protein (BMP) signaling. Two osimertinib-resistant EGFR-mutant lines were developed study effects and disruption. Single RNA sequencing isogenic parental osimertinib resistant performed. Additionally, ATAC Cell ENergetIc metabolism by profiling Translation inHibition analysis (SCENITH) used assess promoter chromatin status glycolytic state. found negative correlation between expression survival patients. Treatment or knockdown significantly elevated lines. Single-cell identified subset cells heightened endothelial characteristics altered pyrimidine metabolism, associated resistance. These exhibited slow-cycling behavior, characterized condensation reduced glycolysis. Combining carotuximab, neutralizing antibody, transcriptomic signature, increased accessibility, restored glycolysis compared treatment alone. Mass spectrometry confirmed that carotuximab re-engaged signaling coupling it CD105. Consequently, re-sensitized tumors increasing their mitotic index ERK mouse models. Carotuximab effectively population sensitivity, offering promising strategy managing refractory NSCLC.

Language: Английский

Citations

0
Fexofenadine Overcomes Osimertinib Resistance by Inhibiting c‐Met in Non‐Small Cell Lung Cancer DOI Creative Commons
Kenneth K.W. To, Kwong‐Sak Leung, William C. Cho

et al.

MedComm – Oncology, Journal Year: 2025, Volume and Issue: 4(2)

Published: April 14, 2025

ABSTRACT Osimertinib is the only third‐generation EGFR tyrosine kinase inhibitor clinically approved for first‐line treatment of advanced NSCLC patients harboring mutations. However, drug resistance severely hinders its clinical efficacy. Acquired MET amplification an important mechanism causing osimertinib resistance. This study first to identify fexofenadine, originally indicated allergic rhinitis and chronic urticaria, as a putative Met‐inhibitor by in silico chemical‐protein interactome analysis known Met inhibitors. Fexofenadine was verified inhibit recombinant cell‐free assay phosphorylation other downstream signaling molecules osimertinib‐resistant cell lines. KINOME profiling revealed similar inhibition profile between fexofenadine Met‐inhibiting cabozantinib using Spearman rank‐order correlation analysis. Among tested lines, most efficacious potentiating NCI‐H820 (having EGFR‐T790M mutation). Transcriptome that differentially expressed genes following were enriched epithelial‐mesenchymal transition‐related biological pathways. Importantly, also shown significantly potentiate antitumor effect drug‐refractory patient‐derived tumor xenograft model NSG mice, without inducing notable adverse effects. These findings advocate evaluation repurposing overcome

Language: Английский

Citations

0
The Evolving Paradigm of Antibody–Drug Conjugates Targeting the ErbB/HER Family of Receptor Tyrosine Kinases DOI Creative Commons
Peyton C. High, Cara Guernsey-Biddle, Shraddha Subramanian

et al.

Pharmaceutics, Journal Year: 2024, Volume and Issue: 16(7), P. 890 - 890

Published: July 2, 2024

Current therapies targeting the human epidermal growth factor receptor (HER) family, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are limited by drug resistance systemic toxicities. Antibody-drug conjugates (ADCs) one of most rapidly expanding classes anti-cancer therapeutics with 13 presently approved FDA. Importantly, ADCs represent a promising therapeutic option potential to overcome traditional HER-targeted therapy delivering highly potent cytotoxins specifically HER-overexpressing cancer cells exerting both mAb- payload-mediated antitumor efficacy. The clinical utility is exemplified immense success HER2-targeted trastuzumab emtansine deruxtecan. Still, strategies improve upon existing as well development against other HER family members, particularly EGFR HER3, great interest. To date, no HER4-targeting have been reported. In this review, we extensively detail clinical-stage EGFR-, HER2-, HER3-targeting monospecific novel pre-clinical bispecific (bsADCs) directed family. We close discussing nascent trends in HER-targeting ADCs, ADC payloads ligand-targeted ADCs.

Language: Английский

Citations

3
In silico exploration of anticancer plant phytochemicals for EGFR-targeted lung cancer therapy DOI

Chaity Debnath Dipa,

Sharika Hossain,

Md. Nazim Uddin Chy

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

Abstract Background: Mutations in the epidermal growth factor receptor (EGFR), particularly tyrosine kinase domain such as exon 19 deletions and L858R point mutation, play a critical role development of non-small cell lung cancer (NSCLC). EGFR is well-established therapeutic target management NSCLC. Methods: In this study, we targeted mutated (L858R) using its crystal structure (PDB ID: 2EB3) to design inhibitors (TKIs). We curated library 687 phytoconstituents from four anticancer plants (Camellia sinensis, Curcuma longa, Ginkgo biloba, Vitis vinifera) IMPPAT database. Kaempferol, morin, isorhamnetin, all emerged promising candidates. Drug-likeness ADMET analyses were performed evaluate pharmacokinetic safety profiles these compounds. Pharmacophore modeling bioactivity score analysis also conducted. Finally, molecular dynamics (MD) simulations assess stability EGFR-ligand complexes. Findings: The docking studies revealed high binding energies for kaempferol (-8.5 kcal/mol), morin isorhamnetin (-8.7 kcal/mol) with active site, compared reference drug, erlotinib (-6.9 kcal/mol). These compounds exhibited superior properties, including gastrointestinal absorption non-inhibition P-glycoprotein activity, unlike erlotinib. Toxicity predictions showed mild immunotoxicity demonstrating no hepatotoxicity inhibition CYP3A4 or CYP2D6 enzymes. Structural highlighted hydroxyl groups selected key hydrogen bond (H-bond) formation residues, enhancing their inhibitory potential. MD confirmed complexes compounds, showing lower average RMSD values better convergence EGFR-erlotinib complex. Conclusion: This research underscores potential kaempferol, novel derived biloba NSCLC treatment. demonstrated strong affinities, favorable in silico. Further vitro vivo validation necessary confirm efficacy against

Language: Английский

Citations

0