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Department of Medicine, Harbor-UCLA Medical Center/UCLA School of Medicine, Torrance, California 90502 [E. A. C., H. S., M. S. K.], Division of Dermatology, Martin Luther King Jr./Charles Drew Medical Center [M. S. K.], Crump Institute for Molecular Imaging & Department of Molecular and Medical Pharmacology [A. D., S. S. G.], and Department of Biomathematics [S. S. G.], UCLA School of Medicine, Los Angeles, California 90095
The Ras-Raf-MAPK pathway is constitutively activated in the majority of melanomas because of a mutation in the BRAF gene. It has been hypothesized that activation of this pathway is crucial for the genesis and maintenance of melanoma and therefore represents an attractive clinical target for metastatic disease. We synthesized a previously characterized MAP kinase kinase inhibitor to test the effect that blocking the Ras-Raf-MAPK pathway would have on the establishment and maintenance of melanoma metastases. Oral administration of CI 1040 inhibited formation of pulmonary metastases and caused rapid regression of established pulmonary metastases in the mouse. Our findings indicate that Ras-Raf-MAPK activation provides crucial signals for the survival of melanoma cells at ectopic sites and that the pharmacological inhibition of this pathway is a promising target for melanoma therapy.
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