Most gastrointestinal stromal tumors (GISTs) are driven by mutations to the KIT or PDGFRA genes. But some 10%-15% of GISTs show no mutation to these or other canonical oncogenes. They are instead characterized by the functional loss of the mitochondrial succinate dehydrogenase (SDH) complex caused by mutation of an SDH subunit or—remarkably—epigenetic silencing without any sign of a causal mutation. In both cases, the SDH loss results in genome-wide DNA hypermethylation. Ludwig Harvard’s Bradley Bernstein, Co-director George Demetri and colleagues described in a 2019 Nature study how these epigenetic changes alter DNA packaging to induce the oncogenic expression of fibroblast growth factor (FGF) and activate an autocrine signaling loop through the FGF receptor (FGFR). These findings prompted clinical investigators Priscilla Merriam and Suzanne George of the Dana-Farber Cancer Institute to launch a phase 2 trial evaluating the responses of SDH-deficient GIST patients to the FGFR inhibitor rogaratinib. They reported, along with Brad and George, the results of this trial in a May publication in Nature Medicine. Two dozen patients received rogaratinib and ten experienced partial responses, for an objective response rate of 41.7%. Median progression-free survival (PFS) was 31.0 months, and 1-year PFS was 77.4%. Toxicities were manageable. The researchers note that their “trial illustrates a successful demonstration of targeted cancer therapy predicated on an epigenetic mechanism of oncogene activation.”
Fibroblast growth factor receptor inhibition for succinate dehydrogenase-deficient gastrointestinal stromal tumors: a phase 2 trial
Nature Medicine, 2026 May 26