Abstract C158: Predicting TKI responses in PDGFRA-mutant gastrointestinal stromal tumor
Authors: Khosroyani Homma M , Town Ajia , Falkenhorst Johanna , Bauer Sebastian , Heinrich Michael 
Published: December 2023

Gastrointestinal stromal tumor (GIST) is the most common sarcoma and frequently harbor oncogenic mutations in the receptor tyrosine kinases KIT or platelet derived growth factor receptor alpha (PDGFRA). Imatinib, a type II tyrosine kinase inhibitor (TKI), can successfully treat many KIT-mutant GIST. Yet, it is generally regarded as less effective against PDGFRA-mutant GIST because patients with the most common mutation, exon 18 D842V, are clinically resistant to imatinib and other GIST type II TKIs. However, there are many other PDGFRA mutations reported in GIST whose imatinib sensitivity is unknown. We curated mutation data from a large cohort of PDGFRA-mutant GIST patients, and over 80% had exon 18 mutations. Many mutations clustered around residues 840-849 and included non-D842V point mutations or complex indels. We previously biochemically profiled some of these frequently observed mutations and showed that some were imatinib sensitive, and that sensitivity was dependent on the properties of the 842-codon residue. As modeling each clinically reported mutation is not feasible, we hypothesized that imatinib sensitivity of PDGFRA exon 18 mutations could be predicted based on the 842 residue. To test our hypothesis, we created individual Ba/F3 cell lines that expressed individual PDGFRA mutant kinases, with one cell line each for every amino acid substitution at the 842 residue. Cells underwent transformation limiting dilution assays and imatinib sensitivity was determined via immunoblotting for phosphorylated and total PDGFRA. We observed that 13 out of the 20 amino acids conferred imatinib sensitivity when in the 842-codon position. 7 out of 8 hydrophobic residues conferred imatinib resistance (IC50&gt;150nM) and all amino acids from other classes (polar, negative charge, positive charge, special case) conferred sensitivity (IC50&lt;150nM). Alanine conferred imatinib sensitivity, despite being hydrophobic. Previous studies describe that imatinib resistance seen in D842V patients is due to PDGFRA structural changes. Therefore, we are currently performing molecular simulations and drug docking studies with our mutant kinases to understand how changes at the 842 position effect kinase structure and imatinib binding. Our predictions will identify patients that would benefit from imatinib therapy, while identifying those that require avapritinib. Avapritinib was recently FDA-approved for first-line treatment of all PDGFRA exon 18 mutation GIST, although it was initially created to target D842V. In Europe, avapritinib is only approved for D842V patients. Identifying non-D842V patients that either require avapritinib or could benefit from imatinib is crucial, as current guidelines may suggest no treatment at all. Also, eligible patients treated with imatinib first have additional treatment options if they progress, but this avenue is not available for those progressing on avapritinib. Using our work to support this paradigm shifting approach to optimize TKI treatment sequencing for PDGFRA-mutant GIST will transform patient care and clinical outcomes.

Citation Format: Homma M Khosroyani, Ajia Town, Johanna Falkenhorst, Sebastian Bauer, Michael Heinrich. Predicting TKI responses in PDGFRA-mutant gastrointestinal stromal tumor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C158.