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

Purpose: Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase () 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 or mutations, -mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any mutant tumors, including GIST, has limited molecular characterization and drug discovery.

Experimental Design: We describe methods for establishing novel patient-derived -mutant (m) GIST models and interrogated the efficacy of temozolomide on these tumor models and in clinical trials of patients with m GIST.

Results: Molecular and metabolic characterization of our patient-derived m 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 GIST models. Translating our discovery to the clinic, a cohort of patients with -mutant GIST treated with temozolomide ( = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST.

Conclusions: We report the first methods to establish patient-derived m 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 GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic..