Epigenetic changes are common in cancer but targeting them therapeutically remains challenging. In 2019, the Bernstein Lab found that hypermethylation induced by loss of functional SDH results in insulator disruption, allowing enhancers driving expression of ANO1 in interstitial cells of Cajal (the putative GIST cell of origin) to activate expression of the oncogenes FGF3/4. This creates an autocrine signaling circuit through FGF receptors that is critical for tumor cell proliferation (PMID: 31666694).
This finding lead to the first clinical trial testing FGFR inhibition in patients with SDHd GIST by the Bernstein Lab and Dana-Farber clinicians. The results of this Phase 2 trial were positive with a 41.7 percent objective response rate, a 31-month median progression-free survival (PFS), and a one-year PFS of 77.4 percent. They also report potential genetic mechanisms for treatment resistance. The authors conclude that FGFR inhibition is a promising approach for this GIST type.