Function of mutant IDH in cholangiocarcinoma

Intrahepatic cholangiocarcinoma (ICC) is an invasive cancer of the liver bile ducts and is among the most lethal of all human malignancies. It is the second most common type of primary liver tumor and has been rising in incidence worldwide for the past 3 decades. These tumors exhibit a high rate of mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes. These mutations result in a novel enzymatic function: while the wild type enzyme catalyzes conversion of isocitrate to α-ketoglutarate (αKG), mutant IDH leads to the reduction of αKG to R(–)-2-hydroxyglutarate (2-HG). 2-HG inhibits the function of the family of dioxygenase enzymes that utilize αKG as a cofactor, including epigenetic modifiers JmjC family histone demethylases and TET family dioxygenases that mediate DNA demethylation. Recently, we demonstrated that mutant IDH is a specific regulator of the hepatic regenerative response that facilitates progenitor cell activation via silencing HNF4α, which encodes a master regulator of hepatocyte identity and quiescence. By blocking differentiation of these hepatic progenitors, mutant IDH creates a cell population primed for oncogenic transformation. Our present focus is to decipher the metabolic and epigenetic circuitry underlying these phenotypes and to identify vulnerabilities of IDH mutant cancer cells that will inform new therapeutic strategies for this deadly disease.