Abstract IA05: Autophagy prevents fatal nucleotide pool depletion in Ras-driven cancer cells

Autophagy degrades and recycles proteins and organelles essential for quality control and survival in starvation. In genetically engineered mouse models (GEMMs) for Kras-driven lung cancer, autophagy prevents the accumulation of defective mitochondria and promotes tumor growth and malignancy. Autophagy-deficient tumor-derived cell lines (TDCLs) are respiration impaired, starvation sensitive, and glutamine-dependent. To survive starvation, autophagy may eliminate defective mitochondria or supply mitochondrial substrates. Here, we sequenced the mitochondrial genome from Kras-driven lung tumors and found higher mutant allele frequencies without autophagy-related-7 (Atg7). But the low pathogenic allele frequency was insufficient to account for metabolic defects. In starvation, Atg7 deficiency attenuated substrate supply for mitochondrial oxygen consumption and increased nucleotide degradation. The resulting nucleotide pool depletion and energy crisis in starvation was rescued by nucleoside supplementation. Thus the role for autophagy in Kras-driven tumor cells is to provide substrates to mitochondria to maintain nucleotide pools and energy homeostasis, which promotes survival to nutrient limitation.

Citation Format: Eileen White. Autophagy prevents fatal nucleotide pool depletion in Ras-driven cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr IA05.