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

BACKGROUND: 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. RESULTS: The model suggests that lapatinib acts as expected by slowing the transition through G(1 )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, which shows saturation kinetics. CONCLUSION: The model separates quantitatively the cytostatic and cytotoxic effects of lapatinib and may have implications for preclinical studies with other anti-oncogene therapies.