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

Journal article


Saavedra-Garcia, P., Roman-Trufero, M., Al-Sadah, H.A., Blighe, K., Lopez-Jimenez, E., Christoforou, M., Penfold, L., Capece, D., Xiong, X., Miao, Y., Parzych, K., Caputo, V., Siskos, A.P., Encheva, V., Liu, Z., Thiel, D., Kaiser, M.F., Piazza, P., Chaidos, A., Karadimitris, A., Franzoso, G., Snijders, A.P., Keun, H.C., Oyarzun, D.A., Barahona, M. and Auner, H.W. (2021). Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs. PNAS. 118 (17), p. e2018229118. https://doi.org/10.1073/pnas.2018229118
AuthorsSaavedra-Garcia, P., Roman-Trufero, M., Al-Sadah, H.A., Blighe, K., Lopez-Jimenez, E., Christoforou, M., Penfold, L., Capece, D., Xiong, X., Miao, Y., Parzych, K., Caputo, V., Siskos, A.P., Encheva, V., Liu, Z., Thiel, D., Kaiser, M.F., Piazza, P., Chaidos, A., Karadimitris, A., Franzoso, G., Snijders, A.P., Keun, H.C., Oyarzun, D.A., Barahona, M. and Auner, H.W.
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.

KeywordsproteasomemyelomaproteostasisGCN2metabolism
Year2021
JournalPNAS
Journal citation118 (17), p. e2018229118
PublisherNational Academy of Sciences
Digital Object Identifier (DOI)https://doi.org/10.1073/pnas.2018229118
Web address (URL)https://www.pnas.org/content/118/17/e2018229118
Publication dates
Print27 Apr 2021
Publication process dates
Accepted16 Mar 2021
Deposited25 Jun 2021
Accepted author manuscript
License
File Access Level
Open
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