Identification of NNMT as a New Target to Treat Triple-negative Breast Cancer

Abstract Triple-negative breast cancer (TNBC) is the most aggressive disease noted for the development of recurrence, distant metastases and short survival times, particularly and tragically in young women. Mounting evidences indicate that TNBC cells underwent a metabolic rewiring to scavenge the upsurge of reactive oxygen species (ROS) encountered during metastasis in order to survive and metastasis. The overarching goal of this proposal to identify the signaling pathways and metabolic dysregulation governing metastasis in TNBC, and to develop novel intervention to prevent this deadly disease. Recently, we found that a robust induction of nicotinamide N- methyltransferase (NNMT) is concomitant with ROS upsurge when TNBC cells detached from matrix and grown in anchorage-independent manner. NNMT-KO inhibits anchorage-independent growth in vitro, and suppresses tumor growth and metastasis in vivo. Further mechanistic analyses indicate that NNMT-KO induces soaring ROS and promotes ferroptosis by decreasing the levels of NAD(P)+ and glutathione (GSH). We hypothesize that NNMT is a salient molecule to promote NAM uptake and NAD(P)+ synthesis in TNBC cells under anchorage-independent growth, thereby alleviating soaring ROS and protecting them from ferroptosis. Thus, NNMT represents an appealing therapeutic target to inhibit TNBC growth and metastasis. In line with this idea, our newly developed NNMT specific bi-substrate inhibitors present a proof-of-concept as they potently suppressed TNBC growth both in vitro and in vivo. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: 1) to define how NNMT promotes anchorage-independent growth and protects ferroptosis in TNBC; 2) to determine the specificity and potency of NNMT bi-substrate inhibitor in TNBC cells; and 3) to determine NNMT’s function and explore therapeutic potential of NNMT inhibitor in pre-clinical mouse models. We will utilize a wide variety of innovative, complementary and systematic methods to vigorously validate the central hypothesis and achieve the goals of this study. This is multiple PI project combines the Zhou laboratory’s strength in TNBC research with the Huang laboratory’s expertise in drug discovery and medicinal chemistry. Our proposal is innovative and significant, because NNMT represents the Achilles heel of TNBC cells; targeting this key molecule with specific inhibitor offers an immense potential for treating metastatic TNBC in a short future.