Dietary thiamine influences l -asparaginase sensitivity in a subset of leukemia cells

Abstract

Tumor environment influences anticancer therapy response but which extracellular nutrients affect drug sensitivity is largely unknown. Using functional genomics, we determine modifiers of l-asparaginase (ASNase) response and identify thiamine pyrophosphate kinase 1 as a metabolic dependency under ASNase treatment. While thiamine is generally not limiting for cell proliferation, a DNA-barcode competition assay identifies leukemia cell lines that grow suboptimally under low thiamine and are characterized by low expression of solute carrier family 19 member 2 (SLC19A2), a thiamine transporter. SLC19A2 is necessary for optimal growth and ASNase resistance, when standard medium thiamine is lowered ~100-fold to human plasma concentrations. In addition, humanizing blood thiamine content of mice through diet sensitizes SLC19A2-low leukemia cells to ASNase in vivo. Together, our work reveals that thiamine utilization is a determinant of ASNase response for some cancer cells and that oversupplying vitamins may affect therapeutic response in leukemia.

Therapeutic Assessment of Targeting ASNS Combined with l-Asparaginase Treatment in Solid Tumors and Investigation of Resistance Mechanisms

“…Moreover, the combination between asparaginase and GCN2 has been mostly explored in vivo in AML models (a liquid tumor indication with high basal level of asparagine) rather than melanoma . Interestingly, functional genomics experiments in leukemia revealed multiple resistance mechanisms to L-ASNase, based either on transcription factors or on dietary inputs, highlighting the existence of potential lineage-specific mechanisms of resistance.…”

Interplay Between Thiamine and p53/p21 Axes Affects Antiproliferative Action of Cisplatin in Lung Adenocarcinoma Cells by Changing Metabolism of 2-Oxoglutarate/Glutamate

“…However, the role of thiamine deficiency and thiamine supplementation during the anticancer treatments is practically not investigated. A study shows that in a subset of leukemia cells, increasing thiamine elevates the sensitivity to anticancer treatments with asparaginase ( Guarecuco et al, 2020 ). Thiamin is also shown to increase sensitivity of breast cancer cells to radiotherapy in a p53/p21-dependent way ( McLure et al, 2004 ).…”

Targeting Nutrient Dependency in Cancer Treatment

“…Presumably, the anti-cancer effects of dual-enzyme activities of ASNase could be explained by the codependency of glutamine/glutamate and asparagine/aspartate observed in several studies (35,36). In addition to glutamine, thiamine-restriction also sensitizes a subset of leukemia cells to ASNase treatment (37). These findings call for more comprehensive studies on therapeutic response to ASNase.…”