Abstract 2161: Quinolinic acid phosphoribosyl transferase (QPRT) is an essential liability of non-small cell lung cancer

Abstract

Abstract Lung cancer is the second most diagnosed type of cancer and the leading cause of cancer-related mortality. 85% of all lung cancer cases are non-small cell lung cancer (NSCLC), a large proportion of which are only diagnosed at advanced stages (II-IV) due to lack of early diagnostic techniques. Standard first-line treatment for late-stage inoperable NSCLC still is chemotherapy regiments. However, most NSCLC patients fail to respond to these regimens or relapse upon treatment. Thus, there is a pressing need to identify novel therapeutic targets that can more effectively treat NSCLC. Quinolinic acid phosphoribosyl transferase (QPRT) is a rate-limiting enzyme in the tryptophan catabolic pathway which fuels de novo NAD+ production, whose expression as previously been shown to have a prognostic value in certain cancers. Here, we demonstrate that high QPRT levels is a feature of a large proportion of NSCLC cell lines and that QPRT induction occurs in genetically engineered models of NSCLC (KP and KL) when compared to the normal lung. Considering the critical role of NAD+ levels to enable high rates of proliferation, we hypothesized that QPRT induction enables lung cancer cells to thrive. Strikingly, QPRT knockdown in a panoply of NSCLC cell lines results in pronounced suppression of tumor cells both in 2D and 3D conditions. Interestingly, we observe that QPRT suppression does not affect proliferation or cell cycle progression but rather due to pronounced induction of cell death. Surprisingly, while we observed DNA damage upon QPRT suppression, NAD+ levels were not affected by QPRT suppression indicating that QPRT’s effects in NSCLC are independent of its contribution to the NAD+ pools. Together, our results point for QPRT as a novel and effective therapeutic target for NSCLC. Citation Format: Hossein Kashfi, Nathan Ward, Didem Ilter, Stanislav Drapela, Aimee Falzone, Stephen Gardell, Gina M. DeNicola, Ana P. Gomes. Quinolinic acid phosphoribosyl transferase (QPRT) is an essential liability of non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2161.