Abstract 1265: Dysregulated tyrosine kinase Tyro3 signaling in acute myeloid leukemia

Abstract The undesirable outcomes of classical chemotherapy approaches in the treatment of cancer pathogenesis has directed scientists to find more targeted and less toxic therapies. Numerous studies of targeted therapies in cancer have demonstrated that finding target genes that are responsible for cancer pathogenesis can lead to novel targeted cancer therapies. Among these studies, tyrosine kinases have been prominent as effective gene targets. We have employed this approach to study the hematologic malignancy, Acute Myeloid Leukemia (AML). In this study, we aimed to understand how human tyrosine kinase members, as functional drivers of leukemogenesis, promote tumor progression by activating downstream molecules. For this purpose, an RNAi assisted silencing assay was designed in which every individual tyrosine kinase member was silenced and impact on primary AML cell viability was assessed. Bioinformatic interpretation of the data revealed that TYRO3 is one of the genes showing significant sensitivity to silencing in 7.64% of AML cases tested (n = 484). This data is compatible with previous studies showing aberrant expression of TAM family member tyrosine kinases in several human cancers. In addition, immunoblotting was performed to assess TYRO3 protein expression in several AML cell lines. Several AML lines demonstrated higher expression levels of TYRO3. In a strong correlation with this finding, TYRO3 siRNA was able to partially silence the TYRO3 expression especially in those cell lines that have higher expression levels of TYRO3 and due to this silencing we observed decreased cell viability relative to non-specific siRNA suggesting that high expression of TYRO3 provides a cell survival advantage in AML. Even though signaling pathways of other TAM family members and their interactions are described in detail, TYRO3 downstream signaling pathway still remains quite undetermined which makes it an intriguing player in cell survival. There are not many small molecules designed to inhibit TAM tyrosine kinases, but our study shows that successful targeted inhibition of this family of receptor tyrosine kinases may represent a promising avenue to provide opportunities to improve therapeutic approaches for patients with AML. [1] Druker, Brian J. “Imatinib as a paradigm of targeted therapies.” Advances in cancer research 91 (2004): 1-30. Citation Format: Fatma Eryildiz, Jeffrey W. Tyner. Dysregulated tyrosine kinase Tyro3 signaling in acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1265.