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Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs

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Title: Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs
Authors: Saavedra-Garcia, P
Roman-Trufero, M
Al-Sadah, HA
Blighe, K
Lopez-Jimenez, E
Christoforou, M
Penfold, L
Capece, D
Xiong, X
Miao, Y
Parzych, K
Caputo, V
Siskos, AP
Encheva, V
Liu, Z
Thiel, D
Kaiser, MF
Piazza, P
Chaidos, A
Karadimitris, A
Franzoso, G
Snijder, AP
Keun, HC
Oyarzún, DA
Barahona, M
Auner, H
Item Type: Journal Article
Abstract: Cancer cells can survive chemotherapy-induced stress, but how they recover from it is not known. Using a temporal multiomics approach, we delineate the global mechanisms of proteotoxic stress resolution in multiple myeloma cells recovering from proteasome inhibition. Our observations define layered and protracted programmes for stress resolution that encompass extensive changes across the transcriptome, proteome, and metabolome. Cellular recovery from proteasome inhibition involved protracted and dynamic changes of glucose and lipid metabolism and suppression of mitochondrial function. We demonstrate that recovering cells are more vulnerable to specific insults than acutely stressed cells and identify the general control nonderepressable 2 (GCN2)-driven cellular response to amino acid scarcity as a key recovery-associated vulnerability. Using a transcriptome analysis pipeline, we further show that GCN2 is also a stress-independent bona fide target in transcriptional signature-defined subsets of solid cancers that share molecular characteristics. Thus, identifying cellular trade-offs tied to the resolution of chemotherapy-induced stress in tumour cells may reveal new therapeutic targets and routes for cancer therapy optimisation.
Issue Date: 27-Apr-2021
Date of Acceptance: 16-Mar-2021
URI: http://hdl.handle.net/10044/1/87287
DOI: 10.1073/pnas.2018229118
ISSN: 0027-8424
Publisher: National Academy of Sciences
Journal / Book Title: Proceedings of the National Academy of Sciences of USA
Volume: 118
Issue: 17
Copyright Statement: © 2021 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY).
Sponsor/Funder: Amgen (Europe) GmbH
Cancer Research UK
Imperial Health Charity
Cancer Research UK
Engineering & Physical Science Research Council (EPSRC)
Cancer Research UK
Cancer Research UK
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
Imperial College Healthcare NHS Trust- BRC Funding
Syngenta Ltd
Funder's Grant Number: PROTOCOL 20167862
European Union FP7
Keywords: GCN2
Publication Status: Published
Article Number: ARTN e2018229118
Appears in Collections:Department of Immunology and Inflammation
Department of Surgery and Cancer
Applied Mathematics and Mathematical Physics
Faculty of Medicine
Faculty of Natural Sciences

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