Abstract LB051: Quinolinic acid phosphoribosyl transferase (QPRT) expression is an essential liability of non-small cell lung cancer independently of its enzymatic function
Authors: Hossein Kashfi, Didem Ilter, John Lockhart, Julia Spegel, Angelo Nicolaci, Stanislav Drapela, Felicia Lazure, Devesh Raizada, Skylar Robbins, Nadir Sarigul, Nathan Ward, Tumpa Dutta, Elsa R. Flores, Jennifer Binning, Stephen Gardel, Gina M. DeNicola, Ana P. Gomes
Journal: Cancer Research (2025)

Abstract Background: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality. This is in part due to the limited efficacy of current therapeutic modalities. QPRT is a rate-limiting enzyme in the tryptophan catabolism which fuels de novo NAD+ production. Considering the critical role of NAD+ levels to enable high rates of proliferation, we hypothesized that QPRT induction enables lung cancer cells to thrive by its ability to expand the NAD(H) pools. Methods: Protein levels were evaluated by western blot. Proliferation and cell death were evaluated using live cell imaging. Grading of lung tumors was performed with simultaneous segmentation by artificial intelligence. NAD+ and related metabolites as well as isotope tracing analysis were performed by mass spectrometry. Annexin V, treatment with Z-VAD FMK and caspase3/7 assays were used to evaluate apoptosis. Protein interactions were determined by co-immunoprecipitation. For the in vivo study, we used a combination of genetically engineered mouse models (GEMM) of NSCLC as well as orthotopically transplants of NSCLC cells into the lungs of NSG mice. Results: Our data show that high QPRT levels is a feature of a large proportion of NSCLC cell lines as well as in several GEMMs representing the continuum of NSCLC progression. Moreover, QPRT expression significantly increased with the grades of tumor across all the NSCLC GEMMs used. Strikingly, QPRT knockdown in NSCLC result in pronounced cell death induction in both in vitro and in vivo study. Surprisingly, NAD+ levels were not affected by QPRT suppression, suggesting that QPRT’s effects in NSCLC are independent of its contribution to the NAD+ pools. Tracing experiments using labeled NAD+ precursors and further inhibition of NAD+ salvage pathway support this idea, as neither quinolinic acid nor its precursor tryptophan were capable to fuel NAD+ in NSCLC, which was contrast with the other two precursors of NAD+ that work through different pathways. Experiments using tryptophan depletion further reinforced a role for QPRT in enabling NSCLC vitality independently of its catalytic activity. Instead, we mechanistically traced this role of QPRT to its ability to directly regulate apoptosis via interaction with pro-caspase 3, which suppresses caspase 3 activation and blocks apoptosis induction. Conclusions: Our results indicates that NSCLC rely on QPRT to support their vitality in the face of heightened replicative stress or cell-death promoting therapies, in an NAD+-independent manner, pointing for QPRT as a novel and effective therapeutic target for NSCLC. Citation Format: Hossein Kashfi, Didem Ilter, John Lockhart, Julia Spegel, Angelo Nicolaci, Stanislav Drapela, Felicia Lazure, Devesh Raizada, Skylar Robbins, Nadir Sarigul, Nathan Ward, Tumpa Dutta, Elsa R. Flores, Jennifer Binning, Stephen Gardel, Gina M. DeNicola, Ana P. Gomes. Quinolinic acid phosphoribosyl transferase (QPRT) expression is an essential liability of non-small cell lung cancer independently of its enzymatic function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB051.