inhibitors have been developed, their use in PDAC remains limited because of compensatory pathway activation and mutation prevalence. Similarly, whereas EGFR amplification and adaptive signaling bypass pathways decrease the durability of EGFR-targeted therapies, TP53 inactivation and MDM2 axis dysregulation contribute to genomic instability and treatment resistance. Although resistance to chemotherapy and targeted therapies, survival signaling, and metabolic reprogramming are all significantly affected by the PI3K/AKT/mTOR system, the therapeutic results with pathway inhibitors have been mixed. Significantly, these signaling pathways function within a coordinated, interdependent network, wherein single-agent approaches are compromised by crosstalk and feedback activation. This review synthesizes these main signaling axes, emphasizing molecular pathology, including mutation-specific biology, diagnostic techniques such as liquid biopsy and NGS, the role of natural compounds, the tumor microenvironment (TME) in pancreatic cancer (PC), and the limitations noted in therapeutic trials. Novel therapeutic approaches include KRAS-directed degradation techniques, pathway co-inhibition, rational combination methods, and therapy paradigms driven by the TME. To discover new molecules with long-lasting therapeutic effects, a system-level understanding of pathway interactions within the PDAC microenvironment is necessary.
Singh et al. (Tue,) studied this question.