Relapse-Driving AML Cells Exhibit Pyrimidine-Synthesis Dependency

Relapse of acute myeloid leukemia (AML) after chemotherapy-induced remission occurs due to persistence and subsequent regrowth of the few cells that survive treatment. Hypothesizing that these cells would be subject to a severe metabolic bottleneck that may present therapeutic vulnerabilities, van Gastel and colleagues employed a mouse model of AML and performed a metabolomic analysis of AML cells that were treated with induction chemotherapy (cytarabine plus doxorubicin) and harvested during the bottleneck. Comparing these AML cells' metabolome with that of vehicle-treated control AML cells and that of AML cells following relapse revealed that the AML cells from the bottleneck were distinguished by upregulation of “glutamine and glutamine metabolism” and “alanine, aspartate, and glutamate metabolism” pathways. In mouse models of AML, treatment with a broad inhibitor of glutamine-metabolism inhibitor after induction chemotherapy—at the time of the cancer-cell bottleneck—extended survival and caused AML-cell apoptosis, whereas treatment with the glutamine-metabolism inhibitor before the bottleneck had no effect. Isotope-labeling experiments showed that the excess glutamine produced in residual AML cells following induction chemotherapy was used to synthesize glutathione and pyrimidines, but inhibiting glutathione synthesis had no effect on survival in this model, whereas inhibiting pyrimidine synthesis depleted AML cells and extended survival. Another fate of carbon from glutamine was aspartate, also essential for pyrimidine synthesis, and further investigation revealed that AML cells induced bone marrow stromal cells (BMSC) to produce and secrete aspartate. Notably, loss of enzymes involved in synthesis of aspartate from glutamine in BMSCs sensitized AML cells to induction chemotherapy. In four patient-derived xenograft models of AML, treatment with brequinar (an inhibitor of pyrimidine synthesis) two days after the end of induction chemotherapy resulted in greater clearance of AML cells from peripheral blood and bone marrow compared with chemotherapy alone. In summary, this work demonstrates that residual AML cells that survive chemotherapy are under targetable metabolic stress, particularly involving pathways linked to pyrimidine synthesis, providing clues about how to target these relapse-driving cells.

van Gastel N, Spinelli JB, Sharda A, Schajnovitz A, Baryawno N, Rhee C, et al. Induction of a timed metabolic collapse to overcome cancer chemoresistance. Cell Metab 2020;32:391–403.

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