UNC569, a novel small molecule Mer inhibitor with efficacy against acute lymphoblastic leukemia in vitro and in vivo
- Authors
- Christoph, S., Deryckere, D., Schlegel, J., Frazer, J.K., Batchelor, L.A., Trakhimets, A.Y., Sather, S., Hunter, D.M., Cummings, C., Liu, J., Yang, C., Kireev, D., Simpson, C., Norris-Drouin, J., Hull-Ryde, E.A., Janzen, W.P., Johnson, G.L., Wang, X., Frye, S.V., Earp, H.S., and Graham, D.K.
- ID
- ZDB-PUB-130905-22
- Date
- 2013
- Source
- Molecular cancer therapeutics 12(11): 2367-77 (Journal)
- Registered Authors
- Batchelor, Lance, Liu, Jing
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Antineoplastic Agents/pharmacology*
- Cell Line, Tumor
- Gene Expression Regulation, Leukemic/drug effects
- Humans
- Jurkat Cells
- MAP Kinase Signaling System/drug effects*
- Molecular Targeted Therapy
- Neoplasms, Experimental
- Phosphorylation/drug effects
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism*
- Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
- Proto-Oncogene Proteins/antagonists & inhibitors*
- Proto-Oncogene Proteins/metabolism
- Proto-Oncogene Proteins c-akt/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- Pyrazoles/pharmacology*
- Pyrimidines/pharmacology*
- Receptor Protein-Tyrosine Kinases/antagonists & inhibitors*
- Receptor Protein-Tyrosine Kinases/metabolism
- Rhabdoid Tumor/drug therapy
- Rhabdoid Tumor/metabolism*
- Rhabdoid Tumor/pathology
- Teratoma/drug therapy
- Teratoma/metabolism*
- Teratoma/pathology
- Zebrafish
- PubMed
- 23997116 Full text @ Mol. Cancer Ther.
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Although survival rates have improved, patients with certain biological subtypes still have suboptimal outcomes. Current chemotherapeutic regimens are associated with short- and long-term toxicities and novel, less toxic therapeutic strategies are needed. Mer receptor tyrosine kinase is ectopically expressed in ALL patient samples and cell lines. Inhibition of Mer expression reduces pro-survival signaling, increases chemosensitivity, and delays development of leukemia in vivo suggesting that Mer tyrosine kinase inhibitors are excellent candidates for targeted therapies. Brain and spinal tumors are the second most common malignancies in childhood. Multiple chemotherapy approaches and radiation have been attempted, yet overall survival remains dismal. Mer is also abnormally expressed in atypical teratoid/rhabdoid tumors (ATRT), providing a rationale for targeting Mer as a therapeutic strategy. We have previously described UNC569, the first small molecule Mer inhibitor. This manuscript describes the biochemical and biological effects of UNC569 in ALL and ATRT. UNC569 inhibited Mer activation and downstream signaling through ERK1/2 and AKT, determined by western blot analysis. Treatment with UNC569 reduced proliferation/survival in liquid culture, decreased colony formation in methylcellulose/soft agar, and increased sensitivity to cytotoxic chemotherapies. MYC transgenic zebrafish with T-ALL were treated with UNC569 (4 µM for 2 weeks). Fluorescence was quantified as indicator of the distribution of lymphoblasts, which express Mer and enhanced green fluorescent protein. UNC569 induced >50% reduction in tumor burden compared to vehicle- and mock-treated fish. These data support further development of Mer inhibitors as effective therapies in ALL and ATRT.