Targeted therapy in SDH- deficient GIST

Abstract

The medical management of advanced gastrointestinal stromal tumors (GIST) has improved with the development of tyrosine kinase inhibitors (TKIs) targeting KIT and PDGFRA mutations. However, approximately 5-10% of GIST lack KIT and PDGFRA mutations, and about a half are deficient in succinate dehydrogenase (SDH) that promotes carcinogenesis by the cytoplasmic accumulation of succinate. This rare group of GIST primarily occurs in the younger patients than other subtypes, and is frequently associated with hereditary syndromes. The role of TKIs in patients with SDH-deficient GIST is controversial, with conflicting results; thus, there is an urgent need to uncover the disease mechanisms, treatment patterns, and responses to systemic therapy among these patients. Here, based on an extensive literature search, we have provided a rigorous overview of the current evidence on the medical treatment of SDH-deficient GIST.

Keywords: GIST; SDH-deficient; gastrointestinal stromal tumors; succinate dehydrogenase; tyrosine kinase inhibitors.

Figure 1.

Schematic representing the interplay between hypoxia and SDH-deficient malignancies. Loss-of-function of SDH may lead to accumulation of succinate and production of reactive oxygen species. Additionally, succinate can induce hypoxic response in normoxic conditions, a situation known as pseuodohypoxia. HIF, hypoxia-inducible factor; Me, methyl group; PHD, prolyl-hydroxylase domain proteins; SDH, succinate dehydrogenase; TET, ten–eleven translocation.