Projects per year
Epidermal growth factor receptors 1 and 2 (EGFR, ErbB2), and cytosolic Src (c Src) are tyrosine kinases that stimulate cell survival, proliferation and migration and if dysregulated can act as oncogenes. Several tyrosine kinase inhibitors (TKIs) have recently gained approval, but long term treatment with TKIs against a single target often lead to acquired resistance. The aim of this study was to investigate the effect of targeting multiple signalling pathways simultaneously in naïve and TKI-resistant cell lines.
Materials and Methods
The ErbB2 and c-Src genes were sequenced and small interfering RNAs (siRNAs) targeting them were developed. Effective siRNAs as well as ErbB2, Egfr and c-Src TKIs (AG828, gefitinib, GW583340 and saracatinib) were evaluated in canine and feline carcinoma cell lines. The effects of combined RNAi targeting of Egfr, ErbB2 and c-Src were assessed.
Inhibition of c-Src and Egfr inhibited cell proliferation, migration and colony formation in feline and canine carcinoma cell lines while ErbB2 targeting exhibited no effect. Chronic drug exposure with gefitinib and saracatinib lead to resistance which was not associated with ATP binding site mutations. RNA interference (RNAi) strategies targeting Egfr plus ErbB2 and c Src plus either Egfr or ErbB2 showed a synergistic inhibition of cell proliferation. When targeting multiple areas of an oncogene or multiple oncogenes simultaneously significantly lower concentrations of siRNAs were required. Cells rendered resistant by chronic drug exposure were still sensitive to RNAi.
Targeting multiple pathways simultaneously improves growth inhibition, reduces the siRNA concentrations required and are still effective in cells rendered resistant to TKIs.
|Number of pages||1|
|Publication status||Published - 24 May 2014|
|Event||European Society for Veterinary Oncology - Palais Niederosterreich, Vienna, Austria|
Duration: 22 May 2014 → 24 May 2014
|Conference||European Society for Veterinary Oncology|
|Period||22/05/14 → 24/05/14|
- Feline squamous cell carcinoma
- RNA INTERFERENCE
FingerprintDive into the research topics of 'Targeting multiple oncogenes simultaneously improves response to therapy and circumvents acquired resistance to single target tyrosine kinase inhibitors'. Together they form a unique fingerprint.
- 3 Finished
1/10/12 → 31/03/13
Studies on the inhibition of feline EGFR in squamous cell carcinoma: Enhancement of radiosensitivity and rescue of resistance to small molecule inhibitorsBergkvist, G., Argyle, D. J., Pang, L. Y., Muirhead, R. & Yool, D. A., 1 Jun 2011, In: Cancer Biology and Therapy. 11, 11, p. 927-937 11 p.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile
Expression of and prognostic role of Ki67 and epidermal growth factor receptor (EGFR) in feline oral squamous cell carcinomas (FOSCC)Bergkvist, G., Argyle, D., Morrison, L., MacIntyre, N., Hayes, A., Shaw, D. & Yool, D., 2010, p. 467. 1 p.
Research output: Contribution to conference › Abstract