Abstract
Simple SummaryAmong 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.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.
Highlights
With the identification of activating mutations of either KIT or platelet-derived growth factor receptor (PDGFRA) tyrosine kinases as main players in gastrointestinal stromal tumors (GIST) pathogenesis and development, in few years, imatinib has become the backbone for the treatment of unresectable and advanced GIST, whose efficacy is profoundly affected by the underlying tumor genotype [2,3,4,5]
By immunohistochemical and flow cytometric analyses, Vitiello and colleagues found that PDGFRA-mutant GIST contained more CD45+ and CD8+ cells, with a proportion of immune cells clustered around perivascular structures, a typical feature
To evaluate the potential susceptibility to immunomodulatory-based treatments of the different genotypes, the immunophenoscore (IPS), a machine learning-based classifier based on the expression of HLA genes, immunomodulators, effector, and suppressor cells, capable of predicting the relative sensitivity to immune checkpoint inhibitors (ICIs), was highest in PDGFRA-mutant. All of these findings show that there is growing evidence in favor of the marked immunogenicity of PDGFRA-mutant GIST, likely specific of D842V mutants only, providing a possible proof of principle for testing immune-therapeutic approaches in this subset of GIST patients, which remains poor in terms of therapeutic options [39,40]
Summary
With the identification of activating mutations of either KIT or platelet-derived growth factor receptor (PDGFRA) tyrosine kinases as main players in GIST pathogenesis and development, in few years, imatinib has become the backbone for the treatment of unresectable and advanced GIST, whose efficacy is profoundly affected by the underlying tumor genotype [2,3,4,5]. Figure figure representing representingprimary primaryand and secondary platelet-derived growth factor receptor (PDGFRA) mutations observed in gastrointestinal stromal tumors (GIST). Factor receptor (PDGFRA) mutations observed in gastrointestinal stromal tumors (GIST). PDGFRA, specific hotspot in exon 18 are known as D842V mutations and mutationsmutations and conferoccurring resistancein toaimatinib The fate of this well-defined GIST population has recently changed with the advent. What they are and what they may be in the near future
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