Computational analysis of receptor tyrosine kinase inhibitors and cancer metabolism: implications for treatment and discovery of potential therapeutic signatures

Abstract

Background Receptor tyrosine kinase (RTK) inhibitors are frequently used to treat cancers and the results have been mixed, some of these small molecule drugs are highly successful while others show a more modest response. A high number of studies have been conducted to investigate the signaling mechanisms and corresponding therapeutic influence of RTK inhibitors in order to explore the therapeutic potential of RTK inhibitors. However, most of these studies neglected the potential metabolic impact of RTK inhibitors, which could be highly associated with drug efficacy and adverse effects during treatment. Methods In order to fill these knowledge gaps and improve the therapeutic utilization of RTK inhibitors a large-scale computational simulation/analysis over multiple types of cancers with the treatment responses of RTK inhibitors was performed. The pharmacological data of all eight RTK inhibitor and gene expression profiles of 479 cell lines from The Cancer Cell Line Encyclopedia were used. Results The potential metabolic impact of RTK inhibitors on different types of cancers were analyzed resulting in cancer-specific (breast, liver, pancreas, central nervous system) metabolic signatures. Many of these are in line with results from different independent studies, thereby providing indirect verification of the obtained results. Conclusions Our study demonstrates the potential of using a computational approach on signature-based-analysis over multiple cancer types. The results reveal the strength of multiple-cancer analysis over conventional signature-based analysis on a single cancer type. Electronic supplementary material The online version of this article (10.1186/s12885-019-5804-0) contains supplementary material, which is available to authorized users.

Erlotinib can halt adenine induced nephrotoxicity in mice through modulating ERK1/2, STAT3, p53 and apoptotic pathways

“…Obtained results showed an elevation in serum urea level in erlotinib group suggesting a metabolic impact of erlotinib as a tyrosine kinase inhibitor on liver cells. Previous studies on cancer cell lines showed an effect of tyrosine kinase inhibitors on N-acetylglutamate synthase a key enzyme in the urea cycle 26 , 27 . We also postulate that erlotinib may interfere with glutamate incorporation in ERK1/2 stimulatory signals through halting glutamate receptors activation by Src tyrosine kinases 28 , 29 .…”

The Metabolic Mechanism Underlying the Enhancing Effects of Glycine and Tryptophan on Kidney Function: How to Reduce EGFR Inhibitory Effect on AAs

“…Prior studies evaluated tyrosine kinase inhibitors effect on N-acetyl glutamate synthase, which is a urea cycle key enzyme (Li, J. et al, 2019) (Pham-Danis C. et al, 2019. The current study showed that pemetrexed might interfere with glutamate incorporation in ERK1/2 stimulatory signals by halting glutamate receptors activation by Src tyrosine kinases, which may direct glutamate towards the elevation of urea formation in the blood.…”

Erlotinib and Garcinia Cambogia Prevent Adenine Induced Nephrotoxicity in Adult Male Albino Rats Through Modulating EKR1/2, STAT3, and p53 Apoptotic Pathways

“…Tyrosine kinase inhibitors have an impact on the urea cycle enzyme N-acetylglutamate synthase (Li, 2019). By inhibiting glutamate receptors, erlotinib may prevent glutamate from reacting with ERK1/2 stimulatory signals.…”