RAF265 Inhibits the Growth of Advanced Human Melanoma Tumors
A partir de greffes, sur des souris, d'échantillons tumoraux prélevés sur 34 patients atteints d'un mélanome métastatique, cette étude évalue l'efficacité d'un composé appelé RAF265 et identifie des facteurs associés à la réponse au traitement
Purpose:The purpose of this pre-clinical study was to determine the effectiveness of RAF265, a multi-kinase inhibitor, for treatment of human metastatic melanoma and to characterize traits associated with drug response. Experimental Design:Advanced metastatic melanoma tumors from 34 patients were orthotopically implanted to nude mice. Tumors that grew in mice (17/34) were evaluated for response to RAF265 (40 mg/kg, QD) over 30 days. The relation between patient characteristics, gene mutation profile, global gene expression profile, and RAF265 effects on tumor growth, MEK/ERK phosphorylation, proliferation, and apoptosis markers were evaluated. Results:Nine of the 17 tumors that successfully implanted (53%) were mutant BRAF (BRAFV600E/K), while 8 of 17 (47%) were BRAF wild-type (BRAFWT). Tumor implants from 7/17 patients (41%) responded to RAF265 treatment with >50% reduction in tumor growth. Five of the 7 (71%) responders were BRAFWT, of which one carried c-KIT L576P and another N-RASQ61R, while only 2 (29%) of the responding tumors were BRAFV600E/K. Gene expression microarray data from non-implanted tumors revealed responders exhibited enriched expression of genes involved in cell growth, proliferation, development, cell signaling, gene expression, and cancer pathways. While response to RAF265 did not correlate with pERK1/2 reduction, RAF265 responders did exhibit reduced pMEK1, reduced proliferation based upon reduced Ki67, cyclin D1 and PLK1, and induction of the apoptosis mediator BIM. Conclusions: Orthotopic implants of patient tumors in mice may predict prognosis and treatment response for melanoma patients. A sub-population of human melanoma tumors respond to RAF265 and can be characterized by gene mutation and gene expression profiles.