02027nas a2200289   4500000000100000000000100001008004100002260000900043653001400052653003300066653003700099653001100136653003500147653001500182100002200197700001400219700002100233700002200254700001900276700002000295700002100315245006700336300001300403490000700416520130000423022001401723       2025                            d  c202510aCell Line10aDrug Evaluation, Preclinical10aHigh-Throughput Screening Assays10aHumans10ainduced pluripotent stem cells10aProteomics1 aMelpomeni Platani1 aHao Jiang1 aLindsay Davidson1 aSantosh Hariharan1 aRegis Doyonnas1 aAngus I. Lamond1 aJason R. Swedlow00aScreening for variable drug responses using human iPSC cohorts  ae03239530 v203 aWe have developed a laboratory-based drug screening platform that uses a cohort of human induced pluripotent stem cell (hiPSC) lines, derived from different donors, to predict variable drug responses of potential clinical relevance. This builds on recent findings that pluripotent hiPSC lines express a broad repertoire of gene transcripts and proteins, whose expression levels reflect the genetic identity of the donor. We demonstrate that a cohort of hiPSC lines from different donors can be screened efficiently in their pluripotent state, using high-throughput Cell Painting assays. Variable phenotypic responses between hiPSC lines were detected with a wide range of clinically approved drugs, in use across multiple disease areas. Furthermore, information on mechanisms of drug-cell interactions underlying the observed variable responses was derived by using quantitative proteomic analysis to compare sets of hiPSC lines that had been stratified objectively, based upon variable response, Cell Painting data. We propose that information derived from comparative drug screening, using curated libraries of hiPSC lines from different donors, can help to improve the delivery of safe new drugs suitable for a broad range of genetic backgrounds and sexual diversity within human populations.  a1932-6203