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Combi-Seq: Multiplexed transcriptome-based profiling of drug combinations using 1deterministic barcoding in single-cell droplets

By Lukas Mathur, Bence Szalai, Ramesh Utharala, Martine Ballinger, Jonathan JM Jonathan, Michael Ryckelynck, Vladimit Benes, Julio Saez-Rodriguez, Christoph A. Merten

Posted 17 Sep 2021
bioRxiv DOI: 10.1101/2021.09.16.460212

Anti-cancer therapies often exhibit only short-term effects. Tumors typically develop drug resistance causing relapses that might be tackled with drug combinations. Identification of the right combination is challenging and would benefit from high-content, high-throughput combinatorial screens directly on patient biopsies. However, such screens require a large amount of material, normally not available from patients. To address these challenges, we developed a scalable microfluidic workflow to screen hundreds of drug combinations in picoliter-size droplets using transcriptome changes as a readout for drug effects. We devised a deterministic combinatorial DNA barcoding approach to encode treatment conditions, enabling the gene expression-based readout of drug effects in a highly multiplexed fashion. We applied our method to screen the effect of 420 drug combinations on the transcriptome of K562 cells using only ~250 single cell droplets per condition, to successfully predict synergistic and antagonistic drug pairs, as well as their pathway activities.

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