Dual NAMPT–KRAS Targeting Emerges as a Promising Strategy in PDAC | CancerNetwork
Introduction
KRAS remains the dominant oncogenic driver in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic targeting of KRAS has produced only modest and often short-lived responses due to rapid adaptive resistance. As KRAS-directed therapies move into clinical development, understanding and overcoming metabolic escape mechanisms has become a major priority in pancreatic cancer research.
Problem Statement
Although pan-RAS inhibitors such as daraxonrasib have shown activity in KRAS-driven PDAC, tumor adaptation and acquired resistance remain major limitations. Emerging evidence suggests that KRAS inhibition induces metabolic rewiring, allowing tumor cells to shift survival dependence toward alternative pathways, thereby reducing the durability of RAS-directed therapy.
Summary
This AACR 2026 report highlights a promising metabolic co-targeting strategy in PDAC based on simultaneous inhibition of KRAS signalling and NAD salvage metabolism. Preclinical work presented by Azmi and colleagues showed that KRAS inhibition induces compensatory metabolic dependence on the NAMPT–NAD pathway, creating a therapeutically exploitable vulnerability. Dual targeting with the NAMPT inhibitor RPT-E-037 and the pan-RAS inhibitor daraxonrasib produced greater tumor regression, enhanced tumor cell death and longer survival in preclinical PDAC models compared with KRAS inhibition alone. Notably, RAS inhibitor–resistant PDAC models demonstrated increased sensitivity to NAMPT inhibition, supporting NAMPT as a biologically plausible resistance target and suggesting a strategy to extend the durability of KRAS-directed therapy. The combination also offers the potential to reduce required RAS inhibitor dosing, which may improve tolerability and enable longer treatment exposure. These findings position metabolic co-targeting as a compelling next step in KRAS-driven PDAC and support early clinical translation of combined NAMPT and pan-RAS inhibition, with phase 1 evaluation anticipated in 2027.
