Gene context drift identifies drug targets to mitigate cancer treatment resistance.

Abstract:: Cancer treatment often fails because combinations of different therapies evoke complex resistance mechanisms that are hard to predict. We introduce REsistance through COntext DRift (RECODR): a computational pipeline that combines co-expression graph networks of single-cell RNA sequencing profiles with a graph-embedding approach to measure changes in gene co-expression context during cancer treatment. RECODR is based on the idea that gene co-expression context, rather than expression level alone, reveals important information about treatment resistance. Analysis of tumors treated in preclinical and clinical trials using RECODR unmasked resistance mechanisms -invisible to existing computational approaches- enabling the design of highly effective combination treatments for mice with choroid plexus carcinoma, and the prediction of potential new treatments for patients with medulloblastoma and triple-negative breast cancer. Thus, RECODR may unravel the complexity of cancer treatment resistance by detecting context-specific changes in gene interactions that determine the resistant phenotype.

Authors:: A Jassim, BV Nimmervoll, S Terranova, E Nathan, L Hu, JT Taylor, KE Masih, L Ruff, M Duarte, E Cooper, G Katyal, M Akhbari, RJ Gilbertson, JC Coleman, JS Toker, C Terhune, G Balmus, SP Jackson, H Liu, T Jiang, MD Taylor, K Hua, JE Abraham, MG Filbin, A Hill, A Patrizi, N Dani, A Regev, MK Lehtinen, RJ Gilbertson

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