Activation of
receptor tyrosine kinases (RTK) plays a key role in the prognosis of
mammary cancer.
Lapatinib is a small molecule dual RTK inhibitor that targets
epidermal growth factor receptor (EGFR) and
human epidermal growth factor receptor 2 (HER2). Identifying the
protein targets involved in the effects of
lapatinib and other RTK inhibitors might help determine why preventive efficacy varies. In this study, female Sprague-Dawley rats were given
methylnitrosourea (MNU) by
intravenous injection resulting in the development of multiple
estrogen receptor-positive
tumors. Treatment with
lapatinib beginning 5 days after MNU was highly effective in preventing
cancer development. In addition, we treated rats with palpable mammary
tumors with
lapatinib daily. In these
tumor-bearing animals, treatment continued for 42 days and therapeutic results were obtained. Some rats bearing
cancers were treated for 5 days, and the resulting lesions were examined for
biomarker modulation.
Lapatinib effectively suppressed the abundance of HER2, phosphorylated HER2 (Tyr1221/1222), and phosphorylated EGFR (Tyr1173, Tyr1110) compared with
tumors from untreated rats.
Protein array analyses allowed parallel determination of the effect of
lapatinib on the relative levels of
protein phosphorylation and
proteins associated with apoptosis. These results combined with immunoreactivity data indicated that, in addition to EGFR and HER2,
lapatinib treatment was associated with changes in a number of other signaling molecules, including IGF-1R, Akt, and downstream targets such as GSK3, p27, p53, and
cyclin D1 presumably leading to impaired proliferation, apoptosis, or cell-cycle arrest.