Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) is an inherited cancer syndrome caused by germline pathogenic variants in the fumarate hydratase (FH) gene. Affected individuals are at risk for developing cutaneous and uterine leiomyomas and aggressive FH-deficient renal cell carcinoma (RCC) with a papillary histology. Due to a disrupted TCA cycle, FH-deficient kidney cancers rely on aerobic glycolysis for energy production, potentially creating compensatory metabolic vulnerabilities. This study conducted a high-throughput drug screen in HLRCC cell lines, which identified a critical dependency on nicotinamide adenine dinucleotide (NAD), a redox cofactor produced by the biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT). Human HLRCC tumors and HLRCC-derived cell lines exhibited elevated NAMPT expression compared to controls. FH-deficient HLRCC cells, but not FH-restored HLRCC or normal kidney cells, were sensitive to NAMPT inhibition. HLRCC cell line viability was significantly decreased in both 2D and 3D in vitro cultures in response to the clinically relevant NAMPT inhibitor OT-82. NAMPT inhibition in vitro significantly decreased the total amount of NAD+, NADH, NADP, NADPH, and PAR levels and the effects of NAMPT inhibition could be rescued by the downstream NAD precursor nicotinamide mononucleotide, confirming the on-target activity of OT-82. Moreover, NAMPT inhibition by OT-82 in two HLRCC xenograft models resulted in severely reduced tumor growth. OT-82 treatment of HLRCC xenograft tumors in vivo inhibited glycolytic flux as demonstrated by reduced lactate/pyruvate ratio in hyperpolarized 13C-pyruvate magnetic resonance spectroscopic imaging experiments. Overall, our data define NAMPT inhibition as a potential therapeutic approach for FH-deficient HLRCC-associated renal cell carcinoma.
Molecular cancer therapeutics. 2024 Oct 14 [Epub ahead of print]
Susana S Najera, Christopher J Ricketts, Laura S Schmidt, Julia I Medina, Keita Saito, Lilia Ileva, Jeffrey R Brender, Amy M James, Cody J Peer, Brad Gouker, Baktiar O Karim, Olga Chernova, Catherine Wells, Ming-Hui Wei, Youfeng Yang, Xiaohu Zhang, Carleen Klumpp-Thomas, Jameson Travers, Lu Chen, Kelli M Wilson, Sameer H Issaq, William D Figg, Simone Difilippantonio, Joseph D Kalen, Murali C Krishna, Craig J Thomas, Michele Ceribelli, Christine M Heske, Daniel R Crooks, Jordan L Meier
National Cancer Institute, Bethesda, MD, United States., Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Bethesda, MD, United States., Frederick National Laboratory for Cancer Research, Frederick, MD, United States., National Cancer Institute, Bethesda, United States., Leidos Biomedical Research Inc., Frederick, MD, United States., National Cancer Institute, Bethesda, Maryland, United States., FNLCR, MHL, Frederick, MD, United States., Oncotartis, Buffalo, NY, United States., National Institutes of Health, National Cancer Institute, Bethesda, MD, United States., National Center for Advancing Translational Sciences, Rockville, MD, United States., National Center for Advancing Translational Sciences, Rockville, United States., National Center for Advancing Translational Sciences, United States., NCATS, NIH, Rockville, United States., Leidos Biomedical Research Inc.,Frederick National Laboratory for Cancer Research, Frederick, MD, United States., National Institutes of Health, Rockville, md, United States., National Institutes of Health, Bethesda, MD, United States.