Using in vitro models to predict TKI sensitivities of PDGFRA-mutant gastrointestinal stromal tumor

The majority of PDGFRA-mutant gastrointestinal stromal tumors (GIST) harbor exon 18 mutations, most commonly D842V, which is treated with avapritinib (a new type I TKI) but is resistant to imatinib and other type II TKIs used to treat GIST. As other complex exon 18 non-D842V, 842-position mutations have been observed, it was previously assumed that these would also be type II TKI resistant, and while much remained unknown and not well-documented, there was clinical evidence of successful imatinib treatment in some cases. Unfortunately, avapritinib is either unavailable or inaccessible to many exon 18 PDGFRA-mutant GIST patients worldwide, therefore I investigated whether imatinib could be used instead as first-line therapy, as it is more accessible and cost-effective. My dissertation describes a novel and comprehensive study of the use of in vitro models to predict TKI sensitivities of exon 18 mutations based on the 842-position amino acid and how structural changes at this position modulate TKI type-specific sensitivities. These findings provide paradigm-shifting evidence that can be integrated into clinical decisions to further individualize the treatment of PDGFRA-mutant GIST and improve clinical outcomes.