Abstract
The transcriptional scaffolds C-terminal Binding Proteins (CtBP) 1 and 2 are overexpressed and act as oncogenic dependencies in multiple cancers but importantly encode a chemically targetable dehydrogenase domain. CtBP promotes survival of high grade serous ovarian carcinoma (HGSOC) cells by repressing expression of Death Receptors (DR) 4 and 5, which activate caspase 8-dependent apoptosis. We have previously developed a series of substrate competitive CtBP dehydrogenase inhibitors active in multiple cell and preclinical solid tumor models. In the current study, we validated CtBP1 and 2 overexpression in a longitudinal series of primary and metastatic/recurrent HGSOC cases. Our lead CtBP dehydrogenase inhibitor, JW-98, induced apoptosis and exhibited variable single agent IC50 values in HGSOC cell lines. Importantly, depletion of nicotinamide adenine dinucleotide (NAD) species using the NAD synthesis inhibitor GMX1778 strikingly sensitized HGSOC cells to JW-98 treatment. Mechanistically, the JW-98/GMX1778 combination effectively abrogated CtBP dimerization that requires stoichiometric levels of intracellular NAD and is required for CtBP's oncogenic transcriptional activities. Highlighting translational potential in late-stage HGSOC, combined JW-98/GMX1778 treatment of platinum-resistant OVCAR3 HGSOC mouse xenografts abrogated tumor growth without observable toxicity. Combined inhibition of CtBP and NAD synthesis represents a novel therapeutic strategy that could improve outcomes in chemoresistant HGSOC.