Kinomic profiling approach identifies Trk as a novel radiation modulator.

Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology
John S JarboeChristopher D Willey

Abstract

Ionizing radiation treatment is used in over half of all cancer patients, thus determining the mechanisms of response or resistance is critical for the development of novel treatment approaches. In this report, we utilize a high-content peptide array platform that performs multiplex kinase assays with real-time kinetic readout to investigate the mechanism of radiation response in vascular endothelial cells. We applied this technology to irradiated human umbilical vein endothelial cells (HUVEC). We identified 49 specific tyrosine phosphopeptides that were differentially affected by irradiation over a time course of 1h. In one example, the Tropomyosin receptor kinase (Trk) family members, TrkA and TrkB, showed transient activation between 2 and 15 min following irradiation. When we targeted TrkA and TrkB using small molecule inhibitors, HUVEC were protected from radiation damage. Conversely, stimulation of TrkA using gambogic amide promoted radiation enhancement. Thus, we show that our approach not only can identify rapid changes in kinase activity but also identify novel targets such as TrkA. TrkA inhibition resulted in radioprotection that correlated with enhanced repair of radiation-induced damage while TrkA stimulation by gam...Continue Reading

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Citations

Jun 20, 2014·Cancer Biotherapy & Radiopharmaceuticals·Ruby F MeredithSharon A Spencer
Dec 20, 2014·International Journal of Oncology·Timothy D RohrbachChristopher D Willey
May 13, 2014·Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology·Joshua C AndersonChristopher D Willey
May 2, 2014·Brain Research·Jennifer L McGuireRobert E McCullumsmith
Apr 30, 2017·American Journal of Physiology. Heart and Circulatory Physiology·Jason L GuichardLouis J Dell'Italia
Apr 11, 2018·Glycobiology·Jie ShiRoland J Pieters
Oct 15, 2021·Life Science Alliance·Sofian Al ShboulPaul M Brennan

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