Integrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells

TitleIntegrated genetic and metabolic landscapes predict vulnerabilities of temozolomide resistant glioblastoma cells
Publication TypeJournal Article
Year of Publication2021
AuthorsImmanuel, SRupa Chris, Ghanate, AD, Parmar, DS, Yadav, R, Uthup, R, Panchagnula, V, Raghunathan, A
Journalnpj Systems Biology and Applications
Volume7
Issue1
Pagination2
Date PublishedJAN
Type of ArticleArticle
Abstract

Metabolic reprogramming and its molecular underpinnings are critical to unravel the duality of cancer cell function and chemo-resistance. Here, we use a constraints-based integrated approach to delineate the interplay between metabolism and epigenetics, hardwired in the genome, to shape temozolomide (TMZ) resistance. Differential metabolism was identified in response to TMZ at varying concentrations in both the resistant neurospheroidal (NSP) and the susceptible (U87MG) glioblastoma cell-lines. The genetic basis of this metabolic adaptation was characterized by whole exome sequencing that identified mutations in signaling pathway regulators of growth and energy metabolism. Remarkably, our integrated approach identified rewiring in glycolysis, TCA cycle, malate aspartate shunt, and oxidative phosphorylation pathways. The differential killing of TMZ resistant NSP by Rotenone at low concentrations with an IC50 value of 5 nM, three orders of magnitude lower than for U87MG that exhibited an IC50 value of 1.8 mM was thus identified using our integrated systems-based approach.

DOI10.1038/s41540-020-00161-7
Type of Journal (Indian or Foreign)

Foreign

Impact Factor (IF)4.187
Divison category: 
Chemical Engineering & Process Development

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