Pancreatic ductal adenocarcinoma (PDAC) is a characteristically aggressive tumour resistant to chemotherapy, and at the centre of this malignant phenotype lies an almost universal dependency on activating mutations in the KRAS oncogene. More than 90 %of PDAC tumours present with alterations in the KRAS oncogene, most frequently at codon 12, and these mutations represent the primary cause of the tumour’s signalling complexity, metabolic heterogeneity and stromal orchestration. The predominance of KRAS in PDAC reflects the capacity of mutant KRAS to adversely affect cellular processes in the tumour microenvironment that sustain the tumour’s growth, plasticity, survival and resistance to therapy. The biochemical behaviour of KRAS is rooted in its role as a molecular switch cycling between inactive GDP-bound and active GTP-bound conformations. In physiologically normal cells, this transition is carefully modulated by guanine nucleotide exchange factors and GTPase-activat...