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• W2040805859 abstract "Molecular subtype is a critical determinant of therapeutic approaches in breast cancer. The subtype is based on the expression of three receptors: The Her2/ErbB2 receptor tyrosine kinase (RTK), whose over-expression defines the HER2amp subtype, and the estrogen or progesterone nuclear hormone receptors, whose over-expression defines the HR+ subtype. Triple negative breast cancers (TNBCs) express low levels of all three receptors. HER2amp status serves as a biomarker for therapy with anti-Her2/ErbB2 antibodies such as trastuzumab or pertuzumab and HR+ status is a biomarker for therapy with hormone receptor antagonists such as tamoxifen. TNBCs are usually treated with cytotoxic chemotherapy. However, breast cancer subtypes are heterogeneous, clinical and mRNA subtypes are not identical, and even the best available biomarker, HER2amp status, correctly predicts response to trastuzumab in only a subset of patients.Projects such as the Cancer Cell Line Encyclopedia aim to identify drug response determinants by relating dose-response profiles for multiple compounds to genomic features across cancer cell collections. Recent studies have suggested that measures of target activity such as phosphorylation are more correlated with drug response than mutation status or gene expression, and steady-state protein data is becoming available for tumors and cell lines. However, few studies have tried to relate the biochemistry of signal transduction to drug response on a large scale, mainly because the measurements are demanding and the utility of the approach is unproven.In this work, we ask whether measurement of the basal and perturbed states of immediate-to-early signaling proteins in serum-starved cells, a robust measurement that can be collected with relatively little biological variability, is predictive of tumor subtype as well as of drug response. We measured the abundance and basal phosphorylation state of nuclear and cell surface receptors and of downstream signaling kinases in the standardized NCI-ICBP43 cell line collection. Because perturbation reveals features of signal transduction that are not apparent by steady state profiling, and because biological ligands present in the microenvironment can alter drug sensitivity, we also collected response profiles by exposing cells to a diverse set of growth factors and cytokines and measuring the activities of downstream signaling kinases before and after ligand addition. We present how the resulting set of ∼3×105 receptor and cell response measurements segregated with clinical subtype and how these proteomic measurements predict the sensitivity of cells to a range of targeted anti-cancer drugs.Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-05-01." @default.
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• W2040805859 date "2013-12-15" @default.
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• W2040805859 title "Abstract P6-05-01: Basal and induced receptor profiles cluster cell lines into subtypes and predict drug response in a panel of breast cancer lines" @default.
• W2040805859 doi "https://doi.org/10.1158/0008-5472.sabcs13-p6-05-01" @default.
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