Within the tumour microenvironment (TME), cancer cells undergo extensive metabolic reprogramming to meet the heightened energy and biosynthetic requirements of uncontrolled cell growth and proliferation. The metabolic state of a cancer cell is dictated by the interplay between cell-intrinsic factors, such as genetic alterations, and cell-extrinsic factors, including altered nutrient availability. The abnormal vasculature and hetero-cellular nutrient competition that exists in solid tumours has long supported the hypothesis that the TME is nutrient deplete. Due to this, cancer cells rely on various nutrient sensing pathways to sense and respond to fluctuations in extracellular nutrient availability. Glucose is a key metabolic fuel that is frequently depleted in the TME across multiple tumour types. Despite this, the molecular mechanisms employed by cancer cells to withstand glucose scarcity remain poorly understood. Previous research investigating the cellular response to glucose deprivation has employed cell culture models which do not accurately recapitulate metabolite availability and diversity in vivo. Using a cell culture model with enhanced physiological relevance, we have employed a multi-omics approach, including transcriptomic and proteomic profiling, to characterise novel adaptive molecular mechanisms employed by cancer cells to withstand glucose deprivation. Interestingly, the majority of alterations in protein expression observed in response to glucose deprivation were not reflected at the transcriptional level. For example, at the protein level, glucose deprivation induced upregulation of RNA and protein methyltransferase proteins, while at the transcriptional level their encoding mRNAs were suppressed. These results post-transcriptional regulatory mechanisms play an important role in cellular response to glucose deprivation. Moreover, an RNA-binding protein known to regulate a post-transcriptional RNA-processing mechanism known as alternative polyadenylation (APA) was significantly downregulated under glucose deprivation. Indeed, using Poly(A)-Click Sequencing we have demonstrated that cancer cells exhibit widespread alterations in APA in response to glucose deprivation. In future experiments, we aim to identify and interrogate post-transcriptional mechanisms, such as APA, which may regulate protein expression under glucose deprivation and determine whether these mechanisms are necessary for cellular adaption and survival in low glucose environments.