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Development of novel small molecule MerTK and Flt3 tyrosine kinase inhibitors for treatment of acute leukemia
- Source :
- Annals of Oncology. 26:ii6
- Publication Year :
- 2015
- Publisher :
- Elsevier BV, 2015.
-
Abstract
- Background: Studies investigating the potential utility of novel small molecule dual MerTK and Flt3 inhibitors (MRX TKIs1) as therapy for AML and ALL will be presented. Methods: MerTK and Flt3 phosphorylation were measured using enzymatic and cell-based assays. Induction of apoptosis was determined using flow cytometry and colony-forming potential was assessed in methylcellulose or soft agar cultures. Orthotopic xenografts were generated in NOD/Scid/IL-2 gamma mice using a luciferase-expressing derivative of the 697 B-ALL cell line, the Molm14 AML cell line, or a Molm14 derivative with the FLT3-ITD D835Y or F691L mutation. Orthotopic patient-derived xenografts (PDX) were generated from primary AML samples. Inhibition of MerTK in bone marrow leukemia cells was assessed by immunoblot. Disease burden was measured using bioluminescence imaging or flow cytometry and median survival was determined. Results: MRX TKI inhibited MerTK and Flt3 with nanomolar potency and had limited off-target activity against 300 other kinases. MRX TKI decreased pro-survival signaling, induced apoptosis, and reduced colony-forming potential in leukemia cells. In B-ALL xenografts, MRX TKI inhibited MerTK phosphorylation in leukemic blasts leading to a dose-dependent reduction in tumor burden and a 2- to 3-fold increase in survival. MRX TKI also increased sensitivity to methotrexate, a chemotherapy currently used for treatment of ALL, resulting in reduced tumor burden and a 50% increase in survival compared to either agent alone. In a MerTK-expressing AML PDX, treatment with MRX TKI resulted in disease regression in blood, spleen, and bone marrow and a 2-fold increase in survival. MRX TKI was similarly effective in xenograft models of FLT3-ITD AML. Importantly, MRX TKI has activity against clinically-relevant FLT3 mutants that mediate resistance to current FLT3 TKIs. Conclusions: The very high potency, relative selectivity, oral bioavailability, target inhibition, and therapeutic efficacy mediated by MRX TKIs in MerTK and FLT3-dependent murine models, both alone and in combination with chemotherapy, support continued development of a dual MerTK/Flt3 inhibitor for treatment of acute leukemia.
Details
- ISSN :
- 09237534
- Volume :
- 26
- Database :
- OpenAIRE
- Journal :
- Annals of Oncology
- Accession number :
- edsair.doi...........2d2363e82cc88bb7d0b4cdae7de4910b
- Full Text :
- https://doi.org/10.1093/annonc/mdv082.2