학술논문
A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma
Document Type
article
Author
Patrik Johansson; Cecilia Krona; Soumi Kundu; Milena Doroszko; Sathishkumar Baskaran; Linnéa Schmidt; Claire Vinel; Elin Almstedt; Ramy Elgendy; Ludmila Elfineh; Caroline Gallant; Sara Lundsten; Fernando J. Ferrer Gago; Aleksi Hakkarainen; Petra Sipilä; Maria Häggblad; Ulf Martens; Bo Lundgren; Melanie M. Frigault; David P. Lane; Fredrik J. Swartling; Lene Uhrbom; Marika Nestor; Silvia Marino; Sven Nelander
Source
Cell Reports, Vol 32, Iss 2, Pp 107897- (2020)
Subject
Language
English
ISSN
2211-1247
Abstract
Summary: 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.