A mathematical model separates quantitatively the cytostatic and cytotoxic effects of a HER2 tyrosine kinase inhibitor

Monday, 5 March 2007

Peter Hinow
Department of Mathematics
Vanderbilt University


Oncogene signaling is known to deregulate cell proliferation resulting in uncontrolled growth and cellular transformation. Gene amplification and/or somatic mutations of the HER2/Neu (ErbB2) proto--oncogene occur in approximately 20% of breast cancers. A therapeutic strategy that has been used to block HER2 function is the small molecule tyrosine kinase inhibitor lapatinib. Using human mammary epithelial cells that overexpress HER2, we determined the anti-proliferative effect of lapatinib through measuring the total cell number and analyzing the cell cycle distribution. A mathematical model was used to interpret the experimental data. The model suggests that lapatinib acts as expected by slowing the transition through G1 phase. However, the experimental data indicated a previously unreported late cytotoxic effect, which was incorporated into the model. Both effects depend on the dosage of the drug in a linear-saturating fashion. The model separates quantitatively the cytostatic and cytotoxic effects of lapatinib and may have implications for preclinical studies with other anti-oncogene therapies.

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