Quantitative proteomics profiling reveals activation of mTOR pathway in trastuzumab resistance

Oncotarget
Wenhu LiuYi Wang

Abstract

Trastuzumab is an antibody-based therapy drug targeting HER2-overexpressing tumors. While it has been proven to be very successful initially, most patients eventually develop resistance to trastuzumab. The mechanism of drug resistance is not well understood. Identifying pathways that mediate trastuzumab resistance will improve our understanding of the underlying mechanism and is crucial for the development of therapeutic strategies to overcome resistance.Here we report a quantitative proteomics profiling of a trastuzumab-sensitive (T-S) gastric cancer cell line NCI N87 and a trastuzumab-resistant NCI N87 (T-R) subline generated by low-dose, continuous trastuzumab treatment. By identifying proteins differentially expressed in these two cell lines, we show that multiple pathways including mTOR, Wnt, DNA damage response and metabolic pathways are significantly altered. We further confirm by western blotting that protein levels of multiple components of the mTOR pathway, including mTOR, AKT and RPS6KB1, are increased, whereas AKT1S1 is decreased, suggesting the activation of mTOR pathway. Importantly, treatment of AZD8055, an mTOR inhibitor, leads to the decreased phosphorylation levels of mTOR downstream molecules RPS6KB1 at Thr42...Continue Reading

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Citations

Mar 7, 2020·Nature Reviews. Drug Discovery·Hanna G Budayeva, Donald S Kirkpatrick
Jun 25, 2020·Acta Neuropathologica·Neelam YounasInga Zerr
Dec 30, 2020·Cell Biology International·Ju-Xian TangDuan Xiao
Aug 14, 2019·Seminars in Cancer Biology·Avaniyapuram Kannan Murugan
Oct 5, 2020·Life Sciences·Sadegh FattahiHaleh Akhavan-Niaki

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Methods Mentioned

BETA
proteomic profiling
PCA
GTPase
protein assay

Software Mentioned

Web Gestalt
Cytoscape
Xcalibur
WEB
Fast
WebGestalt
Proteome Discoverer
based Gene Set Analysis Toolkit
Mascot
quan

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