Vitamin C selectively kills KRAS and BRAF mutant colorectal cancer cells by targeting GAPDH

More than half of human colorectal cancers (CRCs) carry either KRAS or BRAF mutations and are often refractory to approved targeted therapies. We found that cultured human CRC cells harboring KRAS or BRAF mutations are selectively killed when exposed to high levels of vitamin C. This effect is due to increased uptake of the oxidized form of vitamin C, dehydroascorbate (DHA), via the GLUT1 glucose transporter. Increased DHA uptake causes oxidative stress as intracellular DHA is reduced to vitamin C, depleting glutathione. Thus, reactive oxygen species accumulate and inactivate glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Inhibition of GAPDH in highly glycolytic KRAS or BRAF mutant cells leads to an…

• UD
  U.S. Department of Defense
• DR
  Damon Runyon Cancer Research Foundation
• NI
  National Institutes of Health

  Award: P01 CA120964
• NC
  National Cancer Institute

  Awards: P01 CA117969-09, P01 CA120964-07