Transgenic models are predictive: the herceptin and flavopiridol experience

Intact cyclin D₁ functions are essential for transformation by erbB2. We have used transgenic models, tissue culture experiments and human tumor samples to particularly address the role of cyclin D₁–cyclin dependent kinase interactions in transformation by erbB2. The p16 tumor suppressor specifically blocks cyclin dependent kinase 4 (Cdk4) activity and blocked tumorigenesis by erbB2, demonstrating that deregulation of the cyclin dependent kinase partner of cyclin D₁ is an essential target of erbB2. We then investigated the uses of a candidate drug that inhibits Cdk4 in erbB2-mediated tumorigenesis. Individual drugs active against ErbB2 and cyclin D₁ (Herceptin and flavopiridol) were synergistically cytotoxic against ErbB2-positive breast cancer. The addition of flavopiridol to Herceptin synergistically lowered erbB2 levels in these cells. Our data suggest the potential use of combinations of cyclin dependent kinase inhibitors and Herceptin in breast cancer and form the basis for an ongoing trial of this drug combination.