Exploring the repurposing potential of telmisartan drug in breast cancer: an in-silico and in-vitro approach

Kumar, Urwashi; Aich, Jyotirmoi; Devarajan, Shine

doi:10.1097/cad.0000000000001509

Cited by 4 publications

(1 citation statement)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A2M (Alpha-2-Macroglobulin) has been shown to affect adhesion, migration, and growth by inhibiting signaling pathways such as PI3K/AKT and SMAD, while also increasing PTEN levels by down-regulating miR-21 33 . AGTR1 is a poorly described gene in breast cancer that has recently gained attention as a potential target for drug repurposing 34 . Lastly, the HER2-low signature appears to perform equally well in identifying HER2-low cases in both HR-positive and HR-negative tumors, although the low number of HR-negative cases prevented conclusive analyses.…”

Section: Discussionmentioning

confidence: 99%

A gene expression-based classifier for HER2-low breast cancer

Di Cosimo,

Pizzamiglio,

Ciniselli

et al. 2024

Sci Rep

View full text Add to dashboard Cite

In clinical trials evaluating antibody-conjugated drugs (ADCs), HER2-low breast cancer is defined through protein immunohistochemistry scoring (IHC) 1+ or 2+ without gene amplification. However, in daily practice, the accuracy of IHC is compromised by inter-observer variability. Herein, we aimed to identify HER2-low breast cancer primary tumors by leveraging gene expression profiling. A discovery approach was applied to gene expression profile of institutional INT1 (n = 125) and INT2 (n = 84) datasets. We identified differentially expressed genes (DEGs) in each specific HER2 IHC category 0, 1+, 2+ and 3+. Principal Component Analysis was used to generate a HER2-low signature whose performance was evaluated in the independent INT3 (n = 95), and in the publicly available TCGA and GSE81538 datasets. The association between the HER2-low signature and HER2 IHC categories was evaluated by Kruskal–Wallis test with post hoc pair-wise comparisons. The HER2-low signature discriminatory capability was assessed by estimating the area under the receiver operating characteristic curve (AUC). Gene Ontology and KEGG analyses were performed to evaluate the HER2-low signature genes functional enrichment. A HER2-low signature was computed based on HER2 IHC category-specific DEGs. The twenty genes included in the signature were significantly enriched with lipid and steroid metabolism pathways, peptidase regulation, and humoral immune response. The HER2-low signature values showed a bell-shaped distribution across IHC categories (low values in 0 and 3+; high values in 1+ and 2+), effectively distinguishing HER2-low from 0 (p < 0.001) to 3+ (p < 0.001). Notably, the signature values were higher in tumors scored with 1+ as compared to 0. The HER2-low signature association with IHC categories and its bell-shaped distribution was confirmed in the independent INT3, TCGA and GSE81538 datasets. In the combined INT1 and INT3 datasets, the HER2-low signature achieved an AUC value of 0.74 (95% confidence interval, CI 0.67–0.81) in distinguishing HER2-low vs. the other categories, outperforming the individual ERBB2 mRNA AUC value of 0.52 (95% CI 0.43–0.60). These results represent a proof-of-concept for an observer-independent gene-expression-based classifier of HER2-low status. The herein identified 20-gene signature shows promise in distinguishing between HER2 0 and HER2-low expressing tumors, including those scored as 1+ at IHC, and in developing a selection approach for ADCs candidates.

show abstract

Section: Discussionmentioning

confidence: 99%

A gene expression-based classifier for HER2-low breast cancer

Di Cosimo,

Pizzamiglio,

Ciniselli

et al. 2024

Sci Rep

View full text Add to dashboard Cite

show abstract

Repurposing drugs targeting metabolic diseases for cancer therapeutics

Pillai

Ray

Maan

et al. 2023

Drug Discovery Today

View full text Add to dashboard Cite

Interaction of telmisartan and related sartans with the programmed cell death-ligand 1 (PD-L1) protein dimer: a molecular docking analysis

Vergoten,

Bailly

2023

Futur J Pharm Sci

View full text Add to dashboard Cite

BackgroundTelmisartan (TLT) is a prototypic angiotensin receptor blocker largely used to treat hypertension worldwide. In addition to its cardioprotective effects, TLT presents pleiotropic activities and notably displays noticeable anti-inflammatory and antitumor effects. The repression of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint may be implicated antitumor action of TLT, as it is the case with many other compounds equipped with a biphenyl moiety. We have used molecular modeling to compare the interaction of TLT and derivatives with the PD-L1 dimer protein.ResultsTwo molecules, TLT-dimer and TLT-acylglucuronide, were found to form more stable complexes with PD-L1 than TLT itself. In parallel, the docking analysis performed with a series of 12 sartans led to the identification of Olmesartan as a potential PD-L1 binder. The stacked biphenyl unit of Olmesartan positions the molecule along the groove delimited by the two protein monomers. The flanking tetrazole and imidazole moieties, on each side of the biphenyl unit of Olmesartan, contribute favorably to the protein interaction via specific hydrogen bonding interactions.ConclusionsThe computational analysis suggests a possible binding of Olmesartan to PD-L1 dimer and thus offers novel perspectives for the design of small molecules capable of interrupting the PD-1/PD-L1 immune checkpoint. Experimental studies are warranted to validate the hypothesis.Graphical abstract

show abstract

Exploring the repurposing potential of telmisartan drug in breast cancer: an in-silico and in-vitro approach

Cited by 4 publications

References 45 publications

A gene expression-based classifier for HER2-low breast cancer

A gene expression-based classifier for HER2-low breast cancer

Repurposing drugs targeting metabolic diseases for cancer therapeutics

Interaction of telmisartan and related sartans with the programmed cell death-ligand 1 (PD-L1) protein dimer: a molecular docking analysis

Contact Info

Product

Resources

About