Abstract IA020: Increased mitochondrial DNA mutation burden with age limits lung cancer

Abstract

Abstract Mitochondrial DNA (mtDNA) mutations accumulate with age and are found in some cancers. However, the relationship between cancer and mtDNA mutations, and the pathogenicity of those mutations, is not known. To address this question, we created a new mouse model of non-small cell lung cancer (NSCLC) with an increased mtDNA mutation burden. This model was generated by breeding the NSCLC mice model carrying floxed alleles of p53 and KrasG12D, with the mtDNA mutator mouse bearing a germline polymerase gamma mutation that disables proofreading function (POLGD257A) that is responsible for the accumulation of mtDNA mutations over time. The mutator mice with NSCLC had reduced tumor burden and prolonged survival after tumor induction in comparison to POLG wild type mice with NSCLC. Both tumor and normal tissue from mutator mice had elevated mtDNA mutation burden in comparison to wild type mice. The prolonged survival of POLGD257A mice with NSCLC was even more pronounced in older animals where mtDNA mutation burden was further increased. The same was true for a mouse model with a single pathogenic mtDNA mutation found in mitochondrial disease, indicating that it is not the number of mutations, but rather the disabling of mitochondrial function by mutation that causes reduced tumor growth. This suggested that elevated mtDNA mutation with age may suppress NSCLC. To address the mechanism by which accumulation of mtDNA mutations suppress tumor growth we examined metabolism and immune functions. We found that mtDNA mutations caused tumor cell metabolic dysfunction including increased glycolysis and decreased respiration with dependency of glycose and serine and glycine as carbon sources in vitro. Moreover, mtDNA mutations caused tumor dependence on serine and glycine in vivo. Thus, elevated mtDNA mutation burden with age may increase probability of suppression of mitochondrial function, resulting in specific metabolic dependencies in NSCLC. Thus, tumors with mtDNA mutation accumulation may be susceptible to therapeutic dietary restriction of serine and glycine. Citation Format: Eileen White. Increased mitochondrial DNA mutation burden with age limits lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA020.