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A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma

2020; Cell Press; Volume: 32; Issue: 2 Linguagem: Inglês

10.1016/j.celrep.2020.107897

2639-1856

Patrik Johansson, Cecilia Krona, Soumi Kundu, Milena Doroszko, Sathishkumar Baskaran, Linnéa Schmidt, Claire Vinel, Elin Almstedt, Ramy Elgendy, Ludmila Elfineh, Caroline J. Gallant, Sara Lundsten, Fernando Jose Ferrer Gago, Aleksi Hakkarainen, Petra Sipilä, Maria Häggblad, Ulf Märtens, Bo Lundgren, Melanie M. Frigault, David P. Lane, Fredrik J. Swartling, Lene Uhrbom, Marika Nestor, Silvia Marino, Sven Nelander,

Ubiquitin and proteasome pathways

Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells. We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.