Abstract 5012: Characterizing the functional significance of PDGFRAK385I and PDGFRAK385L extracellular domain mutations in the newly defined myxoid glioneuronal tumor

Abstract In 2021, the World Health Organization (WHO) approved new diagnostic guidelines that stratify central nervous system (CNS) tumors based on molecular, transcriptomic, and epigenetic analysis instead of relying solely on phenotypic characterization and added twenty-two new CNS tumor entities based on these guidelines. Our focus is on one of these newly defined entities—myxoid glioneuronal tumors—a slow growing, mucinous glial tumor defined by a pathognomonic dinucleotide substitution in the extracellular domain of PDGFRA p.K385I/L. PDGFRA p.K385I/L remains a variant of unknown significance, however, constitutive activation of PDGFRA is well established as a pharmacologically actionable, oncogenic driver present in a variety of tumor types. Here we report the functional characterization of PDGFRAK385I and PDGFRAK385L by assessing transforming potential using Ba/F3 cells and immortalized human astrocytes. Our results demonstrate that both p.K385I and K385L substitutions are oncogenic, driving cytokine-independent Ba/F3 cell growth and anchorage-independent colony formation. Western blot analysis of downstream cellular signaling pathways in the absence of PDGF-ligand further confirm the activating nature of these mutations, showing robust phosphorylation of PDGFRA and constitutive phosphorylation of downstream signaling effectors ERK1/2, SHP2, and STAT3. To assess whether PDGFRAK385I and PDGFRAK385L are pharmacologically actionable, we tested multiple tyrosine kinase inhibitors with known activity against PDGFRA aberrant cancers using our mutant-transformed PDGFRA Ba/F3 cells. We found that the PDGFRAK385I and PDGFRAK385L mutants were sensitive to inhibitors axitinib, AZD-3229, and avapritinib at therapeutically relevant concentrations. Further, these mutants showed resistance to imatinib, nilotinib, and crenolanib underscoring the importance of pharmacogenomic investigation. No appreciable difference in sensitivity or resistance profiles was observed between the two mutants. In summary, our findings indicate that these previously uncharacterized p.K385I/L extracellular domain mutations in PDGFRA are oncogenic and represent a pharmacologically actionable target that could be harnessed to increase therapeutic options in the setting of myxoid glioneuronal tumors. Citation Format: Catherine Z. Beach, Romel Somwar, Matthew D. Wood, Monika A. Davare. Characterizing the functional significance of PDGFRAK385I and PDGFRAK385L extracellular domain mutations in the newly defined myxoid glioneuronal tumor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5012.