Neomorphic IDH Heterodimer Mutants: An Underestimated Point in Cancer Pathogenesis

• Published in: Current cancer drug targets
• Main Authors: V Dorovatovskaia, Olga, Yu Oliferenko, Mikhail, A Sorokin, Anatoly, I Sobolev, Daniil, S Stupnikova, Galina, S Sobakin, Danil, N Nikolaev, Eugene, A Popov, Igor, I Pekov, Stanislav
• Format: Journal Article
• Language: English
• Published: Netherlands 28.08.2024
• Subjects: 5-fluorouracil; autophagy; deoxyguanosine kinase; chemotherapy sensitivity; p38 MAPK; Colorectal cancer
• ISSN: 1873-5576
• DOI: 10.2174/0115680096317314240723054739

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 de-pend 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 wild-type and mutant proteoforms directly affects enzyme neomorphic activity, cell metabolic por-trait, 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 pro-teoforms 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.