Abstract 2951: Vitamin C is selectively toxic to cancer cells harboring KRAS or BRAF mutations by targeting GAPDH

Abstract

Abstract Although more than half of colorectal cancer patients have either KRAS or BRAF mutations, targeted therapies for these subgroups of cancer patients are still lacking. Here, we report that KRAS or BRAF mutant cells exhibit a significant increase in the uptake of oxidized vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased uptake of DHA in the mutant cell lines causes oxidative stress as intracellular DHA is immediately reduced back to vitamin C by reduced glutathione. Elevated reactive oxygen species inactivate GAPDH and thus divert glycolytic flux into the pentose phosphate pathway. Because KRAS or BRAF mutant cells are highly dependent on glycolysis, this altered glucose metabolism induced by vitamin C ultimately leads to an energy deficit in KRAS or BRAF mutant cells and thereby cell death. There are currently a growing number of clinical trials in phases I/II examining the effect of high dose vitamin C as a treatment for cancers, including colorectal cancers. Our results provide a rationale for the pharmacological use of vitamin C as a therapeutic agent to treat colorectal cancer patients with oncogenic KRAS or BRAF mutations. Citation Format: Jihye Yun, Adam Kavalier, Edouard Mullarky, Kaitlyn Bosch, Jatin Roper, Carlo Rago, Jihye Paik, John Asara, Steven Gross, Bert Vogelstein, Nickolas Papadopoulos, Lewis Cantley. Vitamin C is selectively toxic to cancer cells harboring KRAS or BRAF mutations by targeting GAPDH. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2951. doi:10.1158/1538-7445.AM2014-2951