NAPRT loss promotes lung tumor initiation and growth through AKT signaling independently of NAD+ biosynthesis.

Abstract

Nicotinamide adenine dinucleotide (NAD⁺) metabolism is frequently rewired in cancer, creating metabolic vulnerabilities that can be therapeutically exploited. Loss of nicotinate phosphoribosyltransferase (NAPRT), a rate-limiting enzyme of the Preiss-Handler pathway, renders tumor cells dependent on nicotinamide phosphoribosyltransferase (NAMPT)-mediated NAD⁺ synthesis and serves as a predictive biomarker for NAMPT inhibitor sensitivity. However, whether NAPRT loss actively contributes to tumorigenesis remains unclear. Here, we show that NAPRT depletion promotes tumorigenic phenotypes in lung cancer through a noncanonical mechanism independent of NAD⁺ biosynthesis. NAPRT knockdown enhanced clonogenic initiation, sphere formation, and invasive capacity. Mechanistically, NAPRT loss drives mTORC2-dependent activation of the AKT signaling axis. This effect was not reversed by nicotinic acid or NAD⁺ supplementation or recapitulated by catalytic inhibition of NAPRT, indicating a function distinct from its metabolic role. Pharmacologic AKT inhibition attenuated the enhanced growth induced by NAPRT depletion. In vivo, lung-specific Naprt deletion significantly increased tumor burden in Kras^G12D-driven mice without altering tumor histology or immune cell composition. Together, these findings identify a previously unrecognized tumor-suppressive role for NAPRT in lung tumor initiation and growth.