Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs
File(s)
Published version
Author(s)
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.
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.
Date Issued
2021-04-27
Date Acceptance
2021-03-16
Citation
Proceedings of the National Academy of Sciences of USA, 2021, 118 (17)
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).
License URL
Sponsor
Amgen (Europe) GmbH
Cancer Research UK
Imperial Health Charity
Cancer Research UK
Engineering & Physical Science Research Council (EPSRC)
Cancer Research UK
Cancer Research UK
Bloodwise
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
Imperial College Healthcare NHS Trust- BRC Funding
Syngenta Ltd
Grant Number
PROTOCOL 20167862
27988
FA1819003
C41494/A29035
EP/N014529/1
European Union FP7
27435
15115
15003
RDF01
MR/V027581/1
RDB01
BARAHONA
Subjects
GCN2
metabolism
myeloma
proteasome
proteostasis
Publication Status
Published
Article Number
ARTN e2018229118