Developing synergistic therapeutic strategies targeting deregulated nucleotide metabolism in MYC-driven lymphomas

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Project Summary This project seeks to delineate the way in which PRPS2 (phosphoribosyl pyrophosphate synthetase) LOF results in selective, metabolic vulnerabilities in lymphoma with c-Myc overexpression. The isoforms of phosphoribosyl pyrophosphate synthetase (PRPS1 and PRPS2) are the rate limiting step in de novo nucleotide bio-synthesis as they are the enzymes responsible for the creation of 5-phosphoribosyl-1- pyrophosphate (PRPP) - a necessary component of all nucleotides including ATP, GTP, and IMP. In order to meet c-myc over-expressing cells’ demands for anabolic cellular components, they must have access to increased nucleoside pools. This provides a window of opportunity to use the increased levels of nucleotide bio-synthesis in B-cells with c-myc over-expression as a means of cancer therapy and therefore the focus of this investigation is the phosphoribosyl pyrophosphate synthetase enzyme. Recent studies have found inhibition of nucleotide bio-synthesis via loss of function (LOF) of PRPS2 induces apoptosis in a significant portion of Burkitt’s lymphoma cells. Elucidating the metabolic vulnerabilities demonstrated by PRPS2 LOF will inform the community as to what particular biological need is served by PRPS2 as well as underpin new strategies for combinatorial therapies that target nucleotide biosynthesis. Given the preliminary data generated by our lab, it is known that cell death upon PRPS2 LOF is cell intrinsic and selective- loss of PRPS1 does not result in activation of the apoptotic response. This result has remained consistent in in vitro and in vivo models and provides the basis for further study into ways to exploit this induced synthetic lethality. The most critical objectives of this proposal are to 1) Determine the mechanism by which some Myc overexpressing lymphoma cells evade PRPS2 LOF induced apoptosis and 2) Explore if and how dampened nucleotide biosynthesis sensitizes MYC over expressing malignancies to therapeutics that target nucleotide biosynthesis or nucleoside economy. We hypothesize that PRPS2 LOF produces a synthetic lethality that can be combined with pharmacogenomics approaches targeting de novo/ salvage nucleotide bio-synthetic pathways to induce selective and complete cell death and will analyze this objective through the use of standard dose response curves, cellular viability assays and metabolic fluxomics to determine uptake, rate, and utilization of adenosine through key metabolic pathways, and cellular viability assays to determine the degree of rescue achieved by supplementation. Second, we will determine to what extent does PRPS2 LOF, and therefore dampened nucleotide biosynthesis, combine with existing therapies to ablate lymphomagenesis in the Eμ- Myc mouse model.