Abstract 2708: New approaches to overcome tyrosine kinase inhibitor resistances in chronic myeloid leukemia

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Abstract Chronic myeloid leukemia (CML) is driven by the hyperactive fusion kinase Bcr-Abl, generated by a chromosomal translocation between chromosome 9 and 22. This oncogenic tyrosine kinase builds up its own signaling network with various proteins such as the docking protein Gab2 or the Src kinase Lyn. As a result, the cells become addicted to the constant signals derived from this fusion kinase. This is the reason why selective Bcr Abl tyrosine kinase inhibitors (TKIs), such as Imatinib mesylate or dasatinib, became so successful in the therapy of CML. Despite the great success of these TKIs in CML treatment, TKI resistance remains a serious clinical problem. These resistances can be caused by mutations in the Bcr-Abl oncogene, like the clinical relevant T315I mutation or by aberrant activity of components of the Bcr-Abl signaling network. In that regard, we could show that the overexpression of Gab2 or the expression of a hyperactive mutant of Lyn can confer TKI resistance. Using different CML cell lines and models we aimed to identify new approaches to overcome TKI resistances caused by Bcr-Abl mutations or aberrant downstream signaling. Therefore, we screened inhibitors for their ability to overcome Gab2 mediated resistance or to inhibit the activity of T315I mutated Bcr-Abl. We identified the multikinase inhibitors sorafenib and axitinib, both clinical approved as second line drugs in renal cell or hepatocellular carcinoma, as compounds reducing the viability of Bcr-AblT315I transformed cells. Interestingly, these inhibitors were highly active against TKI resistant Bcr-Abl positive cells in contrast to non-transformed cells. These results invite for the further evaluation of sorafenib and axitinib in the treatment of TKI-resistant CML. Citation Format: Sebastian Halbach, Franziska U. Wöhrle, Sandra Braun, Tilman Brummer. New approaches to overcome tyrosine kinase inhibitor resistances in chronic myeloid leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2708. doi:10.1158/1538-7445.AM2015-2708