Neomorphic IDH Heterodimer Mutants: An Underestimated Point in Cancer Pathogenesis

Mutations in an essential metabolic enzyme, isocitrate dehydrogenase (IDH), were found in many cancers. The impact of IDH1 and IDH2 proteoforms mutations can vary and depend on the cancer type and other genetic alterations. The wild-type IDH1/2 consists of two identical subunits, but the mutant enzyme is a heterodimer of mutant and wild-type subunits, while the mutant homodimer loses its catalytic activity. Thus, the balance of expression of wildtype and mutant proteoforms directly affects enzyme neomorphic activity, cell metabolic portrait, and, therefore, cell survival and proliferation rates. Here, we generalize the influence of the presence of IDH mutations and the expression of mutant and wild-type proteoforms for various nosologies to demonstrate the deficiency in knowledge about the mutual distribution of the proteoforms in cancer cells. The review is supplemented with a brief description of IDH mutations' role in cell metabolic reprogramming and a summary of methods for IDH mutation detection. Eventually, we highlight the necessity of assessing the expression of wild-type and mutated IDH quantitatively, which can help create and deliver personalized approaches for tumor therapy.