Systems level profiling of chemotherapy-induced stress resolution in cancer cells reveals druggable trade-offs
Paula Saavedra-García, Mónica Román-Trufero, Hibah A. Al-Sadah, Kevin Blighe, Elena López‐Jiménez, Marilena Christoforou, Lucy Penfold, Daria Capece, Xiaobei Xiong, Yirun Miao, Katarzyna Parzych, Valentina S. Caputo, Alexandros Siskos, Vesela Encheva, Zijing Liu, Denise Thiel, Martin Kaiser, Paolo Piazza, Aristeidis Chaidos, Anastasios Karadimitris, Guido Franzoso, Ambrosius P. Snijders, Hector C. Keun, Diego A. Oyarzún, Mauricio Barahona, Holger W. Auner
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.