Effects of multi and selective targeted tyrosine kinase inhibitors on function and signaling of different bladder cancer cells

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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

Jörg Hänze¹, Friederike Kessel¹, Pietro Di Fazio²

¹Department of Urology and Pediatric Urology Philipps-University Marburg, Germany.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie

|July 4, 2018

Abstract

Background:

Signaling of receptor tyrosine kinases (RTK) is dysregulated in various malignancies including bladder cancer. RTKs trigger pro-proliferative, anti-apoptotic and metastatic signaling pathways. Here, we assessed the effects of a selective tyrosine kinase inhibitor (TKI) (BGJ398) targeting fibroblast growth factor receptor (FGFR) and a pan-TKI (TKI258) targeting (FGFR), platelet derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR) in bladder cancer cells.

Methods:

Levels of mRNA transcripts were measured in nine human cell lines by quantitative RT-PCR. Cell function was assessed for viability, colony formation, migration, apoptosis and proliferation. Protein mediators of signal transduction were measured by Western-blot.

Results:

mRNA transcripts encoding RTK-related components, transcription factors, epithelial and mesenchymal transition (EMT) markers as well as cell cycle and apoptotic factors were determined in the cell lines. Principal component analysis ordered one epithelial-like cell cluster (5637, BFTC-905, MGHU4, RT112) and one mesenchymal-like cell cluster (T24, UMUC3, HU456, TCC-SUP). Cell response scores towards TKI258 and BGJ398 treatment were heterogeneous between cell lines and correlated with certain transcript levels. Analysis of signal transduction pathways revealed inhibition of fibroblast growth factor receptor (FGFR) signaling and induction of cell cycle dependent kinase (CDKN1A, p21) in epithelial-like cells differing in this regard from responses to mesenchymal-like cells that exhibited inhibition of mitogen-activated protein kinase (MAPK).

Conclusion:

RTK and EMT related transcript analysis separate bladder cancer cells in two clusters. Functional responses towards TKI258 and BGJ398 treatment of bladder Fcancer cells were heterogeneous with deviating effects on signaling and possibly different therapeutic outcome.

Insights

Bladder cancer cells cluster into epithelial and mesenchymal types. Tyrosine kinase inhibitors (TKIs) like BGJ398 and TKI258 show varied effects on these cell clusters, impacting signaling pathways differently and suggesting distinct therapeutic outcomes.

Area of Science:

Oncology
Molecular Biology
Pharmacology

Background:

Receptor tyrosine kinase (RTK) signaling is frequently dysregulated in cancers, including bladder cancer, driving tumor growth, survival, and metastasis.
Investigating targeted therapies like tyrosine kinase inhibitors (TKIs) is crucial for managing bladder cancer.
This study examines the effects of BGJ398 (FGFR inhibitor) and TKI258 (FGFR, PDGFR, VEGFR inhibitor) on bladder cancer cells.

Purpose of the Study:

To assess the impact of BGJ398 and TKI258 on bladder cancer cell lines.
To investigate the correlation between molecular profiles and cellular responses to TKIs.
To explore differential signaling pathway modulation in response to TKI treatment.

Main Methods:

Quantitative RT-PCR was used to measure mRNA transcripts in nine human bladder cancer cell lines.
Cellular functions including viability, proliferation, migration, and apoptosis were assessed.
Western blotting was employed to analyze protein signal transduction mediators.

Main Results:

Bladder cancer cell lines were categorized into epithelial-like and mesenchymal-like clusters based on transcript analysis.
Cellular responses to BGJ398 and TKI258 were heterogeneous and correlated with specific transcript levels.
Epithelial-like cells showed FGFR signaling inhibition and CDKN1A induction, while mesenchymal-like cells exhibited MAPK inhibition.

Conclusions:

RTK and epithelial-mesenchymal transition (EMT) related transcript analysis effectively separates bladder cancer cells into distinct clusters.
Functional responses to TKIs are heterogeneous across bladder cancer cell lines, with differing effects on signaling pathways.
These findings suggest potential for varied therapeutic outcomes based on cellular subtype and TKI response.

Read full analysis

Keywords:

Bladder cancer Cell function Signal transduction Transcript analysis Tyrosine kinase inhibitor

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