Abstract 3005: Comprehensive profile of platelet derived growth factor receptor alpha (PDGFRA) mutations in gastrointestinal stromal tumors

Abstract

Abstract Gastrointestinal stromal tumors (GIST) most commonly harbor oncogenic mutations in KIT tyrosine kinase, which can be targeted by the tyrosine kinase inhibitor, imatinib. However, a subset of GIST, approximately 10% of cases, instead contain mutations in a related kinase, PDGFRA. Historically, advanced PDGFRA-mutant GIST patients have had poor prognosis, primarily because the majority of these tumors are driven by the activating mutation PDGFRA D842V, which is strongly resistant to imatinib and other kinase inhibitors approved for GIST. This amino acid, D842, is within the activation loop of PDGFRA, which contains conserved motifs that change conformation depending on an active or inactive state of the kinase domain. The PDGFRA D842V mutation leads to the loss of polar interactions in the activation loop, which then stabilize the active confirmation of the kinase. Imatinib, a type II kinase inhibitor, binds only to inactive conformation of KIT and PDGFRA. This makes imatinib and other type II kinase inhibitors incapable of binding to the PDGFRA D842V-mutant receptor. The lack of effective treatments for this mutation in particular led to the development of novel kinase inhibitors to target PDGFRA, such as avapritinib (BLU-285), a type I kinase inhibitor which is capable of binding the active conformation and has been shown to potently inhibit PDGFRA D842V in vitro and in the clinic. However, our understanding of the biochemical effect of avapritinib and other PDGFRA inhibitors against all known primary and secondary PDGFRA mutations is still unknown. We have collected clinical data from over 200 PDGFRA-mutant GIST patients, the largest database of its kind to date. We found that over half of all these GIST bear D842V mutations, but nearly 50 unique mutations make up the mutations seen in the remaining GIST cases. Using in vitro models, we profiled the sensitivity of avapritinib and other novel inhibitors such as crenolanib, ripretinib (DCC-2618), and AZD3229 against many of the observed PDGFRA mutations. We also used three-dimensional modeling in silico to demonstrate the consequences of PDGFRA activating mutations on kinase function and drug binding. We also modeled and characterized novel secondary mutations in PDGFRA seen in drug resistant tumors. From our results, we have curated a comprehensive data set that can be used to inform clinicians about possible treatment options for PDGFRA-mutant GIST, and also provide implications for treatments of other PDGFRA-mutant cancers. Citation Format: Homma Khosroyani, Lillian R. Klug, Ajia Town, Jonas Lategahn, Johanna Falkenhorst, Susanne Grunewald, Thomas Mühlenberg, Christiane Ehrt, Eve Wardelmann, Wolfgang Hartmann, Hans-Ulrich Schildhaus, Sascha Jung, Paul Czodrowski, Abbas Agaimy, Piotr Rutkowski, Daniel Rauh, Sebastian Bauer, Michael C. Heinrich. Comprehensive profile of platelet derived growth factor receptor alpha (PDGFRA) mutations in gastrointestinal stromal tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3005.