Targeting metabolic vulnerabilities in therapy- resistant solid and haematopoietic cancers

Abstract

The cellular mechanisms that control protein degradation constitute a non-oncogenic cancer cell vulnerability and, thus, a therapeutic target. Although this proposition is supported by the clinical success of inhibitors of the proteasome, the main effector of intracellular protein degradation in some malignancies, most cancers are resistant to proteasome inhibitors (PIs) and their clinical benefit is limited by varying degrees of primary and acquired resistance. Cancer cells can survive PI- induced proteotoxic stress, but how they resolve it is still unknown. Therefore, I aimed to investigate strategies to optimise the use of PIs. GCN2 is an eIF2α kinase that senses amino acid deprivation and blocks global protein translation, thus conserving energy and amino acids for cells to survive starvation. GCN2 is critical for cancer cell proliferation and modulates angiogenesis in hypoxic and nutrient-depleted tumor regions, thereby promoting their resistance to toxic effects of therapy. Therefore, GCN2 inhibition could be an effective approach to further augment the fatal amino acid shortage caused by PIs and thus could enhance their proteotoxicity, decrease cancer cell survival and overcome their resistance. First, I clarified the role of GCN2 in determining cancer cell fate after proteotoxic insults. I could show that GCN2 promotes cancer cell survival, proliferation and migration under complex conditions of nutrient shortages and/or inhibition of VCP, an essential regulator of protein degradation that when inhibited can trigger fatal proteotoxic stress. Secondly, I studied mechanisms of cellular recovery from proteotoxic stress by performing an extended multi-omics time-course experiment akin to the clinical situation were myeloma cells were treated with a 1 hour pulse of carfilzomib, a second generation PI in clinical use, followed by a wash out and culturing of cells in fresh medium. The data revealed wide-ranging changes across the transcriptome, proteome, and metabolome of recovered cells that persist far beyond immediate stress survival and highlighted the importance of GCN2 and mitochondrial respiration as two recovery mechanisms. Moreover, using a transcriptome analysis pipeline, GCN2 was shown as a proteotoxic stress-independent target in transcriptional signature-defined subset of skin cancer. Therefore, cellular vulnerabilities tied to cancer cells recovery from chemotherapy-induced stress can reveal new therapeutic targets to optimise cancer therapies.