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

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 signaturedefined 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.

Automated summary

The study reveals the complex mechanisms of proteotoxic stress resolution in cancer cells recovering from chemotherapy-induced stress, involving extensive changes across the transcriptome, proteome, and metabolome, as well as dynamic alterations in glucose and lipid metabolism and suppression of mitochondrial function. Additionally, recovering cells are more vulnerable to specific insults, with a key vulnerability associated with cellular response to amino acid scarcity.