Characterization of cancer-associated IDH2 mutations that differ in tumorigenicity, chemosensitivity and 2-hydroxyglutarate production

// Kevin P. Kotredes 1 , Roshanak Razmpour 2 , Evan Lutton 2 , Mercedes Alfonso-Prieto 3 , 4 , 5 , Servio H. Ramirez 2 and Ana M. Gamero 1 1 Department of Medical Genetics and Molecular Biochemistry, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA 2 Department of Pathology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA 3 Department of Inorganic and Organic Chemistry, University of Barcelona, Barcelona, Spain 4 Computational Biomedicine, Institute for Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Julich, Julich, Germany 5 C. and O. Vogt Institute for Brain Research, Medical Faculty, Heinrich-Heine University Dusseldorf, Dusseldorf, Germany Correspondence to: Ana M. Gamero, email: gameroa@temple.edu Keywords: glioblastoma; IDH2; tumorigenesis; chemotherapy; biomarker Received: October 06, 2018     Accepted: March 23, 2019     Published: April 12, 2019 ABSTRACT The family of isocitrate dehydrogenase (IDH) enzymes is vital for cellular metabolism, as IDH1 and IDH2 are required for the decarboxylation of isocitrate to α-ketoglutarate. Heterozygous somatic mutations in IDH1 or IDH2 genes have been detected in many cancers. They share the neomorphic production of the oncometabolite (R)-2-hydroxyglutarate [(R)-2-HG]. With respect to IDH2, it is unclear whether all IDH2 mutations display the same or differ in tumorigenic properties and degrees of chemosensitivity. Here, we evaluated the three most frequent IDH2 mutations occurring in cancer. The predicted changes to the enzyme structure introduced by these individual mutations are supported by the observed production of (R)-2-HG. However, their tumorigenic properties, response to chemotherapeutic agents, and baseline activation of STAT3 differed. Paradoxically, the varying levels of endogenous (R)-2-HG produced by each IDH2 mutant inversely correlated with their respective growth rates. Interestingly, while we found that (R)-2-HG stimulated the growth of non-transformed cells, (R)-2-HG also displayed antitumor activity by suppressing the growth of tumors harboring wild type IDH2. The mitogenic effect of (R)-2-HG in immortalized cells could be switched to antiproliferative by transformation with oncogenic RAS. Thus, our findings show that despite their shared (R)-2-HG production, IDH2 mutations are not alike and differ in shaping tumor cell behavior and response to chemotherapeutic agents. Our study also reveals that under certain conditions, (R)-2-HG has antitumor properties.