No abstract

Anaplastic thyroid cancer (ATC) is one of the most aggressive and lethal tumor types, characterized by loss of differentiation, epithelial-to-mesenchymal transition, extremely high proliferation rate, and generalized resistance to therapy. To identify novel relevant, targetable molecular alterations, we analyzed gene expression profiles from a genetically engineered ATC mouse model and from human patient datasets, and found consistent upregulation of genes encoding enzymes involved in the one-carbon metabolic pathway, which uses serine and folates to generate both nucleotides and glycine. Genetic and pharmacological inhibition of SHMT2, a key enzyme of the mitochondrial arm of the one-carbon pathway, rendered ATC cells glycine auxotroph and led to significant inhibition of cell proliferation and colony forming ability, which was primarily caused by depletion of the purine pool. Notably, these growth-suppressive effects were significantly amplified when cells were grown in the presence of physiological types and levels of folates. Genetic depletion of SHMT2 dramatically impaired tumor growth in vivo, both in xenograft models and in an immunocompetent allograft model of ATC. Together, these data establish the upregulation of the one-carbon metabolic pathway as a novel and targetable vulnerability of ATC cells, which can be exploited for therapeutic purposes.

Anaplastic thyroid cancer (ATC) is one of the most aggressive and lethal tumor types, characterized by loss of differentiation, epithelial-to-mesenchymal transition, extremely high proliferation rate, and generalized resistance to therapy. To identify novel relevant, targetable molecular alterations, we have analyzed gene expression profiles from a genetically engineered ATC mouse model and from two human patient datasets, and have found consistent and coordinated upregulation of several genes encoding enzymes involved in the one-carbon metabolic pathway, which uses serine and folates to generate nucleotides, glutathione and glycine. We have used a combination of cell line and in vivo approaches to assess the role of this pathway in the progression and maintenance of ATC and the effect of its inhibition on tumor behavior. Genetic and pharmacological inhibition of both MTHFD2 and SHMT2, key enzymes of the mitochondrial arm of the one-carbon pathway, rendered mouse and human ATC cells auxotroph for glycine and led to significant inhibition of tumor cell proliferation and colony forming ability, which was primarily caused by depletion of the purine pool leading to arrest in S phase. Notably, these growth-suppressive effects were significantly amplified when cells were grown in the presence of physiological types and levels of folates. Genetic blockage of the one-carbon pathway dramatically impaired tumor growth in vivo, both in immunocompetent allograft models and in immunocompromised xenograft models of ATC. Together, these data establish the upregulation of the one-carbon metabolic pathway as a novel and targetable vulnerability of ATC cells, which can be exploited for therapeutic purposes. Citation Format: Adam J. Sugarman, Luong Do Huynh, Antonio Di Cristofano. Anaplastic thyroid cancer cells upregulate mitochondrial one-carbon metabolism to meet purine demand, eliciting a targetable vulnerability. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4983.