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- W2810071149 abstract "ABSTRACT Introduction Dysregulation of the receptor tyrosine kinases HER2 and Met correlate with poor breast cancer prognosis and invasive aggressive profile. Met amplification proved to be the HER2-dependent tumours inevitable escape mechanism from the anticancer effects of targeted therapies including trastuzumab, and small-molecule RTK inhibitors like lapatinib, gefitinib, and erlotinib. Dual HER2-Met inhibition is expected to be effective and less likely to develop resistance.As a results these unavoidable critical conditions now creates a high demand either to design or identified a lead molecule that can inhibit Met/HER2 combinedly. Material and methods To validate the hypothesis molecular modelling used to identify a Met/HER2 hit from a wide library of natural compounds. Identified hits via virtual screening further validated through cell free Z-LYTE and cell viability assay in a wide range of cancer cell lines. In addition, cytotoxicity tested in non-cancer cell line. Western blot and flowcytometry analysis used to validate the activity of the identified hit at molecular level. Finally, to push the hit into a lead rank used in vivo athymic nude mice in two different xenograft model such as MDA-231, BT-474 in both IP and oral administration. Results and discussions OC showed typical type-I binding mode at Met ATP kinase domain. OC aldehydes, ester, phenol groups showed critical interactions at activation loop ASP1222/TYR1230 and hinge region PRO1158/MET1160. OC uniquely interacting HER2 kinase domain at hinge region MET801, PHE864, THR862 and SER783. OC showed low-µM inhibitory activities against both Met and HER2 kinases in cell-free Z-LYTE assays. In vitro, OC showed inhibition of the proliferation and migrations in BC cells BT-474, SK-BR-3, MDA-MB-231 at low μM IC50 dose range. OC effect on HER2 and MET were further confirmed by Western blotting, flowcytometry studies. OC potently induced autophagy in SK-BR-3 by upregulation of LCA/B, Atg-3, Atg-7, Atg-16L within 6–12 hour treatment. OC had no effect on the viability of the non-tumorigenic MCF-12A and RSC 96 cells. In vivo, 5–10 mg/kg oral/ip dose range of OC potently inhibited 65%–90% tumour growth both BT-474 and MDA-MB-231 BC cells xenograft models. This was further confirmed by significant reductions of Ki-67, CD31in treated animal tumours by IHC. Conclusion Collectively, these promising results suggest that OC is a unique dual Met/HER2 inhibitory lead entity with excellent therapeutic potential to control breast malignancies with aberrant Met or HER2 activity." @default.
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- W2810071149 date "2018-06-01" @default.
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- W2810071149 title "PO-406 The olive-based oleocanthal as a dual HER2-MET inhibitor for the control of breast cancer" @default.
- W2810071149 doi "https://doi.org/10.1136/esmoopen-2018-eacr25.432" @default.
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