Establishment of Patient-Derived Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response.

Abstract

Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase (<i>SDH</i>) subunits (A-D) comprising less than 7.5% (i.e., 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring <i>KIT</i> or <i>PDGFRA</i> mutations, <i>SDH</i>-mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any <i>SDH-</i>mutant tumors, including GIST, has limited molecular characterization and drug discovery. We describe methods for establishing novel patient-derived <i>SDH</i>-mutant (m<i>SDH</i>) GIST models and interrogated the efficacy of temozolomide on these tumor models <i>in vitro</i> and in clinical trials of patients with m<i>SDH</i> GIST. Molecular and metabolic characterization of our patient-derived m<i>SDH</i> GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our m<i>SDH</i> GIST models. Translating our <i>in vitro</i> discovery to the clinic, a cohort of patients with <i>SDH</i>-mutant GIST treated with temozolomide (<i>n</i> = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST. We report the first methods to establish patient-derived m<i>SDH</i> tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with m<i>SDH</i> GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.<i>See related commentary by Blakely et al., p. 3</i>.