Project description:Ex-vivo drug sensitivity screening (DSS) only provides a readout on mixtures of cells, potentially occulting important information on clinically relevant cell subtypes. Here we developed a machine-learning framework to deconvolute bulk RNA expression matched with bulk drug sensitivity into cell subtype composition and cell subtype drug sensitivity. We first determined that our method could decipher the cellular composition of bulk samples more accurately than current state-of-the-art methods. We then optimized an algorithm capable of estimating cell subtype- and single-cell-specific drug sensitivity, which we evaluated by performing in-vitro drug studies
Project description:Ex-vivo drug sensitivity screening (DSS) only provides a readout on mixtures of cells, potentially occulting important information on clinically relevant cell subtypes. Here we developed a machine-learning framework to deconvolute bulk RNA expression matched with bulk drug sensitivity into cell subtype composition and cell subtype drug sensitivity. We first determined that our method could decipher the cellular composition of bulk samples more accurately than current state-of-the-art methods. We then optimized an algorithm capable of estimating cell subtype- and single-cell-specific drug sensitivity, which we evaluated by performing in-vitro drug studies
Project description:Target deconvolution is a crucial but costly and time-consuming task that hinder large-scale profiling for drug discovery. We present a matrix-augmented pooling strategy (MAPS) which mixes multiple drugs into samples with optimized permutation and delineates targets of each drug simultaneously with mathematical processing. We validated this strategy with thermal proteome profiling (TPP) testing of 15 drugs concurrently, increasing experimental throughput by 60x while maintaining high sensitivity and specificity. Benefiting from the lower cost and higher throughput of MAPS, we perform target deconvolution of the 15 drugs across 5 cell lines. Our profiling revealed drug-target interactions can differ vastly in targets and binding affinity across cell lines. We further validated BRAF and CSNK2A are the potential off-targets of bafetinib and abemaciclib, respectively. This work presents the largest target profiling of structurally diverse drugs across multiple cell lines to date.
Project description:Tumor cell lines and drug-resistant counterparts. These data support the publication Gyorffy et al, Oncogene 2005 (July), Prediction of doxorubicin sensitivity in breast tumors based on gene expression profiles of drug-resistant cell lines correlates with patient survival. We contrasted the expression profiles of 13 different human tumor cell lines of gastric (EPG85-257), pancreatic (EPP85-181), colon (HT29) and breast (MCF7 and MDA-MB-231) origin and their counterparts resistant to the topoisomerase inhibitors daunorubicin, doxorubicin or mitoxantrone. We interrogated cDNA arrays with 43 000 cDNA clones ( approximately 30 000 unique genes) to study the expression pattern of these cell lines. A cell type comparison design experiment design type compares cells of different type for example different cell lines. Using regression correlation