Induction of a Timed Metabolic Collapse to Overcome Cancer Chemoresistance

Abstract

Cancer relapse begins at the moment malignant cells pass through the extreme metabolic bottleneck of stress from chemotherapy and the by-products of massive surrounding cell death. In acute myeloid leukemia (AML), complete remissions are common, but few are cured. We tracked AML cells in vivo, defined the moment of maximal response following chemotherapy, captured persisting cells and conducted unbiased metabolic analysis, revealing a metabolite profile distinct from the pre-chemo growth or post-chemo relapse phase. Persisting cells used glutamine in a distinctive manner, preferentially fueling pyrimidine synthesis and glutathione generation, but not oxidative phosphorylation. Notably, malignant cell pyrimidine synthesis also required aspartate provided by specific bone marrow stromal cells. Blunting glutamine metabolism or pyrimidine synthesis selected against residual cells and improved survival in AML mouse models. We propose that timed cell-intrinsic or niche-focused metabolic disruption can exploit a transient vulnerability and induce a metabolic collapse in cancer cells to overcome chemoresistance.