Current management of succinate dehydrogenase-deficient gastrointestinal stromal tumors

Abstract

Gastrointestinal stromal tumors (GISTs) are increasingly recognized as having diverse biology. With the development of tyrosine kinase inhibitors molecularly matched to oncogenic KIT and PDGFRA mutations, GISTs have become a quintessential model for precision oncology. However, about 5-10% of GIST lack these driver mutations and are deficient in succinate dehydrogenase (SDH), an enzyme that converts succinate to fumarate. SDH deficiency leads to accumulation of succinate, an oncometabolite that promotes tumorigenesis. SDH-deficient GISTs are clinically unique in that they generally affect younger patients and are associated with GIST-paraganglioma hereditary syndrome, also known as Carney-Stratakis Syndrome. SDH-deficient GISTs are generally resistant to tyrosine-kinase inhibitors, the standard treatment for advanced or metastatic GIST. Thus, surgical resection is the mainstay of treatment for localized disease, but recurrence is common. Clinical trials are currently underway investigating systemic agents for treatment of advanced SDH-deficient GIST. However, further studies are warranted to improve our understanding of SDH-deficient GIST disease biology, natural history, surgical approaches, and novel therapeutics.

Keywords: GIST; Gastrointestinal stromal tumors; SDH; Succinate dehydrogenase; Tyrosine kinase inhibitors.

Figure 1.. Schematic of the Krebs cycle.

The succinate dehydrogenase (SDH) complex converts succinate to fumarate.

Figure 2.. Complex II in the electron transport chain.

Electrons enter complex II. FAD is then reduced to FADH₂, during the oxidation of succinate to fumarate in SDHA. Electrons are transferred from FADH₂ to iron sulphur proteins in SDHB, and then to ubiquinone (Q) bound to SDHC and SDHD. Ubiquinone is reduced to ubiquinol (QH₂), which transfers electrons to complex III[26].