fig7

Figure 7. Schematic overview of the mechanisms of resistance to KRAS inhibitors in PDAC. Resistance mechanisms are categorized as intrinsic or acquired and include KRAS-dependent alterations (e.g., secondary mutations or amplification of KRAS), KRAS-independent signaling bypass through RTK activation or amplification (e.g., EGFR, MET), reactivation of downstream pathways (including MAPK and PI3K signaling), and TME-mediated mechanisms such as stromal remodeling and immune modulation. These processes collectively sustain tumor cell survival and proliferation despite pharmacological inhibition of KRAS. Created in BioRender. Giovannetti, E. (2026) https://BioRender.com/c2u0n36. PDAC: Pancreatic ductal adenocarcinoma; RTK: receptor tyrosine kinase; EGFR: epidermal growth factor receptor; MET: mesenchymal-epithelial transition factor; MAPK: mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; TME: tumor microenvironment; MEK: mitogen-activated protein kinase kinase; ERK: extracellular signal-regulated kinase; Akt: AKT serine/threonine kinase; mTOR: mechanistic target of rapamycin; GAP: GTPase-activating protein; GDP: guanosine diphosphate; GTP: guanosine triphosphate; GEF: guanine nucleotide exchange factor; ABCB1: ATP-binding cassette subfamily B member 1; CAF: cancer-associated fibroblast.