Annals of Oncology 12:S21-S22, 2001
© 2001 European Society for Medical Oncology
Symposium Article |
Modulation of p27/Cdk2 complex formation through 4D5-mediated inhibition of HER2 receptor signaling
Friedrich Miescher Institute Basel, Switzerland
Correspondence to: H. A. Lane, PhD Friedrich Miescher Institute P.O. Box 2543 4002 Basel Switzerland E-mail: heidi.lane{at}pharma.novartis.com
The molecular mechanisms mediating the anti-proliferative effects of the murine anti-HER2 monoclonal antibody (4D5) were investigated in HER2-overexpressing human carcinoma cell lines. Treatment with 4D5 resulted in a dramatic accumulation of BT-474 breast carcinoma cells in Gl; concomitant with reduced expression of proteins involved in sequestration of the cyclin E/Cdk2 inhibitor protein p27, increased association of p27 with Cdk2 complexes and Cdk2 inactivation. No equivalent effects were observed in BT-474 cells treated with a control, non-inhibitory HER2 monoclonal antibody (FRP5) or in a HER2-overexpressing cell line insensitive to 4D5 treatment (MKN7 gastric carcinoma cells), confirming the relationship between these molecular changes and 4D5-mediated inhibition of proliferation. Increased p27 expression was also observed in 4D5-treated BT-474 cells; however an antisense approach demonstrated that this increase was not required for Cdk2 inactivation or establishment of the Gl block. These data suggest that 4D5 interferes with HER2 receptor signaling, resulting in downregulation of proteins involved in p27 sequestration. This causes release of p27, allowing binding and inhibition of cyclin E/Cdk2 complexes and inhibition of Gl/S progression. This model was confirmed using a second 4D5-sensitive, HER2-overexpressing breast tumor line (SKBR3), and suggests that the dependency of a given tumor cell on elevated HER2-receptor signaling for the maintenance of p27 sequestration proteins may determine the clinical response to treatment with the humanized anti-HER2 monoclonal antibody Herceptin® (trastuzumab).
4D5 antibody, cell cycle, HER2 overexpression, Herceptin, p27, trastuzumab
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