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Figure 4. KRAS-regulated signaling networks controlling autophagy and adaptive responses in PDAC. Under basal conditions, oncogenic KRAS coordinates autophagy regulation through two major downstream pathways: the PI3K–AKT–mTOR axis and the MAPK cascade. Through PI3K–AKT signaling, KRAS promotes mTORC1 activation, which suppresses autophagy initiation by inhibiting ULK1. In parallel, AMPK positively regulates ULK1, promoting autophagy induction under metabolic stress, while MAPK signaling supports tumor growth and metabolic adaptation. Upon pharmacological KRAS inhibition, both MAPK and PI3K–AKT–mTOR signaling are suppressed (greyed out), leading to adaptive rewiring of the system. In this context, loss of mTOR-mediated repression permits sustained ULK1 activation driven by persistent AMPK signaling. This creates strong pro-autophagic pressure, a key adaptive survival mechanism in PDAC. Concurrent MEK inhibition further reinforces MAPK pathway suppression. However, when autophagy is simultaneously inhibited, the autophagic process is blocked downstream despite continued ULK1 activation, thereby eliminating a critical metabolic escape route and promoting tumor cell vulnerability. This schematic illustrates a proposed mechanistic model integrating current preclinical evidence on adaptive signaling and autophagy following KRAS inhibition in PDAC. Created in BioRender. Giovannetti, E. (2026) https://BioRender.com/uu2e1sj. PDAC: Pancreatic ductal adenocarcinoma; PI3K: phosphoinositide 3-kinase; AKT: AKT serine/threonine kinase; mTOR: mechanistic target of rapamycin; MAPK: mitogen-activated protein kinase; mTORC1: mechanistic target of rapamycin complex 1; ULK1: Unc-51 like autophagy activating kinase 1; AMPK: AMP-activated protein kinase; MEK: mitogen-activated protein kinase kinase; RAF: rapidly accelerated fibrosarcoma; ERK: extracellular signal-regulated kinase.