The novel kinase inhibitor EMD1214063 is effective against neuroblastoma.
Children with high-risk neuroblastoma have poor survival rates, and novel therapies are needed. Previous studies have identified a role for the HGF/c-Met pathway in neuroblastoma pathogenesis. We hypothesized that EMD1214063 would be effective against neuroblastoma tumor cells and tumors in preclinical models via inhibition of HGF/c-Met signaling. Methods We determined the expression of c-Met protein by Western blots in a panel of neuroblastoma tumor cell lines and neuroblastoma cell viability after treatment with EMD1214063 using MTT assays. TUNEL assays and assays for DNA ladder formation, were performed to measure the induction of apoptosis after EMD1214063 treatment. Inhibition of intracellular signaling was measured by Western blot analysis of treated and untreated cells. To investigate the efficacy of EMD1214063 against neuroblastoma tumors in vivo, neuroblastoma cells were injected orthotopically into immunocompromised mice, and mice were treated with oral EMD1214063. Tumors were evaluated for growth, histologic appearance, and induction of apoptosis by immunohistochemistry. Results All neuroblastoma cell lines were sensitive to EMD1214063, and IC50 values ranged from 2.4 to 8.5 μM. EMD1214063 treatment inhibited HGF-mediated c-Met phosphorylation and MEK phosphorylation in neuroblastoma cells. EMD1214063 induced apoptosis in all tested cell lines. In mice with neuroblastoma xenograft tumors, EMD1214063 treatment reduced tumor growth. Conclusions Treatment of neuroblastoma tumor cells with EMD1214063 inhibits HGF-induced c-Met phosphorylation and results in cell death. EMD1214063 treatment is also effective in reducing tumor growth in vivo. EMD1214063 therefore represents a novel therapeutic agent for neuroblastoma, and further preclinical studies of EMD1214063 are warranted.
Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX, USA.
Kathy
K
Scorsone
Linna
L
Zhang
Sarah E
SE
Woodfield
John
J
Hicks
Peter E
PE
Zage
D000310:Adrenal Gland Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051379:Mice; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; C582858:EMD1214063; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D019859:Proto-Oncogene Proteins c-met