The Identity of PDGFRA D842V-Mutant Gastrointestinal Stromal Tumors (GIST)

SIMPLE SUMMARY: Among the platelet-derived growth factor receptor (PDGFRA) mutations in gastrointestinal stromal tumors (GIST), the most frequent is the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V), widely recognized as D842V, a two-sided mutation providing primary resistance to all currently approved agents for GIST treatment. In recent years, new specific inhibitors have been studied in preclinical and clinical settings, and molecular findings have been accumulated, well describing this complex entity. This paper aims at offering a comprehensive picture of the clinical features and the molecular background of this rare subtype of GIST. ABSTRACT: The majority of gastrointestinal stromal tumors (GIST) carry a sensitive primary KIT mutation, but approximately 5% to 10% of cases harbor activating mutations of platelet-derived growth factor receptor (PDGFRA), mainly involving the A-loop encoded by exon 18 (~5%), or more rarely the JM domain, encoded by exon 12 (~1%), or the ATP binding domain encoded by exon 14 (<1%). The most frequent mutation is the substitution at position 842 in the A-loop of an aspartic acid (D) with a valine (V) in exon 18, widely recognized as D842V. This mutation, as well known, provides primary resistance to imatinib and sunitinib. Thus, until few years ago, no active drugs were available for this subtype of GIST. Conversely, recent years have witnessed the development of a new specific inhibitor—avapritinib—that has been studied in in vitro and clinical setting with promising results. In light of this primary resistance to conventional therapies, the biological background of D842V-mutant GIST has been deeply investigated to better understand what features characterize this peculiar subset of GIST, and some promising insights have emerged. Hereinafter, we present a comprehensive overview on the clinical features and the molecular background of this rare subtype of GIST.