Relocating job wise? 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 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, 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.