Abstract 1665: Investigating Daple-FLT3 gene fusion in leukemia cells and its response to kinase inhibitors

Abstract Gene fusions are frequently found in leukemia and other cancers. The signaling scaffold protein, Daple (CCDC88C), has been found to undergo gene fusion to the receptor tyrosine kinase, FLT3. Specifically, a fragment of the coiled-coil domain from Daple and tyrosine kinase domain (TKD) of FLT3 are found fused together. How the gene product from this gene fusion functions in rewiring the signaling network in cells and whether this gene product can be targeted though pharmacological inhibitions remain unclear. Cell surface receptors, such as receptor tyrosine kinases (RTKs), activate cell signaling and genetic mutations that lead to constitutive receptor activation can promote unregulated cell proliferation, survival, and migration. Leukemia patients with hyperactive RTKs are treated with tyrosine kinase inhibitors (TKIs), such as Imatinib and Sorafenib. Here we demonstrate how TKIs can directly block the activation of Daple-FLT3 and prevent hyperactivation of its downstream pathways. Our studies unveil a strategy to identify other compounds which may serve as an additive, or alternative, approach to treating patients with Daple gene fusion. Citation Format: Elena Nguyen, Jason Ear. Investigating Daple-FLT3 gene fusion in leukemia cells and its response to kinase inhibitors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1665.