Abstract A85: Concurrent targeting of glutamine and asparagine metabolism produces synergistic inhibition of tumor cell proliferation

One of the best characterized examples of metabolic changes occurring in a wide range of cancer cells is dependence on the non-essential amino acid glutamine. We identified requirements for several other non-essential amino acids, including asparagine, across a panel of glutamine-dependent and –independent breast and lung cancer cell lines. Glutamine and asparagine metabolism are tightly linked. Therefore, we hypothesized that concurrent targeting of the metabolism of these two non-essential amino acids could cooperatively interfere with tumor cell growth. Treatment with a glutaminase inhibitor, BPTES, and concurrent enzymatic depletion of asparagine produced a synergistic antiproliferative effect in many, but not all, cancer cell lines. Mechanistic data suggest that metabolic circuitry gets co-opted to maintain amino acid pools following combined targeting of glutamine and asparagine metabolism, resulting in mitochondrial dysfunction and redox imbalance. Following combination treatment, alterations in mitochondrial metabolism and cystine influx were observed, but overall amino acid levels remained surprisingly stable. These metabolic changes were reflected in cellular functional readouts as measured by Seahorse analysis and measurement of ROS levels. Importantly, they were also linked to the synergistic antiproliferative phenotype. Our results provide new mechanistic insight into the interplay between glutamine and asparagine metabolism in cancer cells and suggest that...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Therapeutic Targets From Cancer: Poster Presentations - Proffered Abstracts Source Type: research