Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs.
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ICR Authors
Authors
Saavedra-García, P
Roman-Trufero, M
Al-Sadah, HA
Blighe, K
López-Jiménez, E
Christoforou, M
Penfold, L
Capece, D
Xiong, X
Miao, Y
Parzych, K
Caputo, VS
Siskos, AP
Encheva, V
Liu, Z
Thiel, D
Kaiser, MF
Piazza, P
Chaidos, A
Karadimitris, A
Franzoso, G
Snijders, AP
Keun, HC
Oyarzún, DA
Barahona, M
Auner, HW
Roman-Trufero, M
Al-Sadah, HA
Blighe, K
López-Jiménez, E
Christoforou, M
Penfold, L
Capece, D
Xiong, X
Miao, Y
Parzych, K
Caputo, VS
Siskos, AP
Encheva, V
Liu, Z
Thiel, D
Kaiser, MF
Piazza, P
Chaidos, A
Karadimitris, A
Franzoso, G
Snijders, AP
Keun, HC
Oyarzún, DA
Barahona, M
Auner, HW
Document Type
Journal Article
Date
2021-04-27
Date Accepted
2021-04-21
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 programs 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 tumor cells may reveal new therapeutic targets and routes for cancer therapy optimization.
Citation
Proceedings of the National Academy of Sciences of the United States of America, 2021, 118 (17)
Source Title
Publisher
NATL ACAD SCIENCES
ISSN
0027-8424
eISSN
1091-6490
Collections
Research Team
Myeloma Group
Myeloma Group
Myeloma Group