Treatment of metastatic melanoma with an orally available inhibitor of the Ras-Raf-MAPK cascade.

Abstract

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.

• Authors: Eric A Collisson, Abhijit De, Hiroyuki Suzuki, Sanjiv S Gambhir, Michael S Kolodney
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 18 Pg. 5669-73 (Sep 15 2003) ISSN: 0008-5472 [Print] United States
• PMID: 14522881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
• Benzamides
• Enzyme Inhibitors
• Oncogene Proteins
• BRAF protein, human
• Braf protein, mouse
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-raf
• Mitogen-Activated Protein Kinases
• MAP Kinase Kinase Kinase 1
• MAP3K1 protein, human
• Map3k1 protein, mouse
• ras Proteins

Topics

• Animals
• Benzamides (pharmacology)
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Humans
• MAP Kinase Kinase Kinase 1
• MAP Kinase Signaling System (drug effects)
• Melanoma (drug therapy, enzymology, genetics, secondary)
• Mice
• Mice, SCID
• Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Oncogene Proteins (genetics)
• Phosphorylation (drug effects)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-raf (antagonists & inhibitors, metabolism)
• Xenograft Model Antitumor Assays
• ras Proteins (antagonists & inhibitors, metabolism)