KRAS-Driven Oncogenic Signalling in Pancreatic Ductal Adenocarcinoma: Molecular Mechanisms, Regulatory Pathways, and Therapeutic Frontiers

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-activating proteins. Activating mutations such as G12D, G12V or G12R reduce the intrinsic GTPase activity of KRAS and disrupt GAP-mediated inactivation, thereby generating a persistently active GTP-associated form that signals without appropriate regulatory restraint. Beyond its altered catalytic behaviour, mutant KRAS demonstrates enhanced stability at the plasma membrane and forms highly ordered nanoclusters that serve as dynamic signalling platforms. These nanoclusters recruit and spatially organise effector proteins, enabling a sustained, amplified and spatially coordinated activation of downstream pathways.

The oncogenic activity of KRAS is transmitted through several major effector cascades that together sustain the malignant phenotype. Central among these is the RAF–MEK–ERK pathway, which drives mitogenic gene expression, cell-cycle progression and proliferative advantage. A parallel axis, the PI3K–AKT–mTOR pathway, contributes to enhanced survival, metabolic flexibility and cellular resilience under nutrient limitation and hypoxia. Additional signalling through RalGEF-RalB circuitry influences vesicle dynamics, cytoskeletal reorganisation, motility and NF-κB-dependent inflammatory programmes. Importantly, these pathways do not operate in isolation. Their convergence and reciprocal compensation create a dense signalling architecture in which inhibiting one cascade frequently leads to adaptive rebound activation in another, explaining why single-agent kinase inhibitors have historically failed to produce durable responses in PDAC.

A key dimension of KRAS-driven tumorigenesis lies in its ability to remodel cellular metabolism in a manner that supports proliferation in a nutrient-deprived and hypoxic environment. Mutant KRAS promotes a marked shift towards aerobic glycolysis, characterised by upregulated glucose transport, enhanced glycolytic flux and reprogrammed pyruvate utilisation. Equally distinctive is the reliance on a non-canonical glutamine metabolic pathway, particularly dependent on aspartate transamination and malate conversion, which sustains NADPH production and preserves redox homeostasis. Lipid biosynthesis is similarly augmented through KRAS-mediated activation of SREBP-driven metabolic programmes, enabling the continued synthesis of membranes and signalling lipids. These metabolic pathways provide not only energy and biosynthetic substrates but also adaptive advantages under the physical and nutritional constraints imposed by PDAC’s desmoplastic microenvironment.

The influence of KRAS extends beyond tumour-intrinsic changes to profoundly shape the surrounding stromal ecosystem. PDAC is characterised by a dense fibrotic stroma composed of cancer-associated fibroblasts, extracellular matrix proteins and infiltrating immune cells, and KRAS signalling plays a central role in sculpting this microenvironment. Through the secretion of cytokines, chemokines and growth factors, KRAS-mutant epithelial cells induce fibroblast activation and drive extracellular matrix deposition, resulting in elevated tissue stiffness and impaired vascular perfusion. These physical properties hinder effective drug delivery and generate mechanical stress that further reinforces malignant behaviour. Concurrently, KRAS-driven inflammatory signalling fosters an immunosuppressive milieu dominated by myeloid cell infiltration, T-cell exclusion and upregulation of immune checkpoint molecules. This immune privilege forms a significant barrier to effective immunotherapy and underscores the interconnectedness of KRAS signalling and immune evasion.

On a transcriptional and epigenetic level, KRAS triggers extensive reprogramming that stabilises the malignant state. It activates transcription factors such as MYC, AP-1 and STAT3, each of which governs broad transcriptional networks that reinforce proliferation, metabolic adaptation and inflammatory signalling. Furthermore, KRAS influences chromatin accessibility by modulating the activity of chromatin remodelers and epigenetic regulators, leading to altered enhancer landscapes and changes in promoter usage. Recent evidence also indicates that KRAS affects RNA biology through mechanisms involving RNA-binding proteins, non-coding RNAs and epitranscriptomic marks such as N6-methyladenosine, collectively altering transcript stability, splicing fidelity and translational efficiency.

The metastatic behaviour of PDAC is also deeply influenced by KRAS, particularly through its capacity to induce epithelial–mesenchymal transition. By upregulating transcriptional repressors of epithelial identity and promoting cytoskeletal rearrangements, KRAS enhances motility, invasion and tissue dissemination. Moreover, KRAS-driven vesicular trafficking and exosomal communication facilitate the conditioning of distant metastatic niches, demonstrating that the oncogene exerts influence far beyond the primary tumour.

Despite its entrenched role in PDAC biology, KRAS remained an elusive therapeutic target for decades due to its structural constraints and the absence of suitable binding pockets. However, recent breakthroughs in the development of allele-specific inhibitors, especially for G12C and now for G12D, have disrupted the long-held paradigm that KRAS is “undruggable.” Additional innovations such as PROTAC-based KRAS degraders, RNA interference strategies, antisense oligonucleotides and synthetic lethality approaches have significantly expanded the therapeutic landscape. Nonetheless, the inherent adaptability of KRAS-driven signalling necessitates rational combination strategies incorporating inhibitors of upstream regulators such as SHP2, downstream effectors such as ERK, and compensatory pathways including autophagy and immune modulation. Future research directions warrant patient-derived organoids, xenograft models and single-cell multi-omic profiling, which will further refine our understanding of KRAS dependencies and accelerate the translation of these targeted therapies.

In conclusion, KRAS serves as the central molecular engine that drives the biological identity of PDAC. Its pervasive effect on cellular signalling, metabolism, tumour microenvironment composition and therapeutic resistance underscores the necessity of understanding KRAS not as a single oncogenic mutation but as a complex regulatory nexus governing tumour evolution. The emerging era of KRAS-targeted therapy, combined with deeper mechanistic insights and integrative systems biology-based approaches, offers an opportunity to redefine the therapeutic landscape of PDAC and address a malignancy long considered insurmountable.

Figure 1. KRAS-centred signalling map with expression-encoded nodes.
The diagram shows the major downstream pathways activated by oncogenic KRAS, including the RAF–MEK–ERK cascade, the PI3K–AKT–mTOR axis and the RalGEF–RalB–NF-κB module. Additional metabolic, immune and EMT-associated targets are included to represent broader KRAS-dependent regulatory outputs. Node fill colours represent relative expression levels (low to high: purple → white → red). Edges denote directed activating interactions, arranged using a Sugiyama hierarchical layout that preserves biological directionality from KRAS toward downstream transcriptional regulators and effector genes.

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