ABERRANT AMINO ACID METABOLISM EXPOSE NOVEL FUNCTIONAL VULNERABILITIES IN GLIOBLASTOMA

Abstract Despite advances in molecularly characterizing glioblastoma, metabolic alterations driving its aggressive phenotype are only beginning to be recognized. Integrative cross-platform analyses coupling global metabolomic and gene expression profiling identified aberrant amino acid (AA) metabolism as a central node in glioblastoma. This metabolic phenotype was recapitulated in preclinical models and through a series of investigations designed to determine the biologic consequence of individual AA, we identified branched chain AA (BCAA) and glutamine as the only indispensable AA in glioblastoma, serving as the sole source of nucleotide pools and glutathione, respectively. Although molecularly and/or chemically perturbing these pathways resulted in cytotoxicity in glioblastoma, normal astrocytes demonstrated a similar response, suggesting therapeutic limitations in targeting these core metabolic pathways in cancer. As the glioblastoma microenvironment typically represents a nutrient-deprived state, we went on to determine the capacity of these cells to adapt to AA restricted conditions by only providing these cells with the above-identified indispensable AA. Intriguingly, glioblastoma cells had the unique ability to revert a state of metabolic dormancy. In addition to triggering a reversible proliferative arrest, this dormant phenotype displayed a near-complete shutdown of glycolysis that allowed these cells to adapt and maintain survival in glucose-deprived conditions and elicited profound resistance to ionizing radiation. Studies designed to systemically understand molecular underpinnings driving this unique metabolically dormant state uncovered a functional reliance upon mTOR/p21 signaling to maintain proliferative arrest in nutrient unfavorable conditions. Consistent with these findings, p21 expression was differentially expressed in the perinecrotic core of glioblastoma when compared to the peripheral edge in patient samples. Targeting this novel functional vulnerability through p21 inhibition, thereby, ‘forcing’ proliferation of these cells in nutrient unfavorable conditions, led to robust cytotoxicity specific to dormant cells and enhanced radiation response. Targeting functional vulnerabilities in otherwise therapeutically resistant cells represents a promising clinical strategy in glioblastoma.