Development of a novel class of agents that induce the degradation of Her2

G Chiosis PhD, M Vilenchik PhD, N Rosen MD PhD, D Solit MD

Memorial Sloan-Kettering Cancer Center, New York, NY, United States

AIM: Overexpression of the transmembrane tyrosine kinase Her2 is associated with aggressive malignancies and several therapeutic strategies targeting the receptor are now in various stages of clinical development. Most of the known agents block the activation or inhibit the activity of the kinase, however, a more significant therapeutic outcome may result from degrading the oncoprotein. METHODS: Here we report the development of a novel class of agents that induce the proteasomal degradation of Her2 by selectively inhibiting the heat shock protein 90 (Hsp90). RESULTS: We present a representative of this class, PU24FCl, that inhibits cancer cell growth, delays progression through the cell cycle, causes Her2-degradation and has profound morphological and functional effects on cancer cells at doses that tightly correlate with its binding affinity for Hsp90. In vivo administration of PU24FCl to mice bearing human breast cancer xenograft tumors causes significant and prolonged degradation of Her2 and results in anti-tumor activity at non-toxic doses. CONCLUSIONS: These findings suggest that this class of agents may represent a new therapeutic strategy for the treatment of Her2-dependent tumors.

Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Nice, France; February 7 - 10, 2004; in oral session 895 (Chemotherapy response).