| Lapatinib is a selective inhibitor of both epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases with IC50 of 10.2 and 9.8 nM, respectively. Lapatinib inhibits receptor signal processes by binding to the ATP-binding pocket of the EGFR/HER2 protein kinase domain, preventing self-phosphorylation and subsequent activation of the signal mechanism.[1] The IC50s of lapatinib range between 100 nM in HER-2-overexpressing UACC-812 breast cancer cells and 18.6 μM in MDA-MB-231 breast cancer cells that express high levels of EGFR. Human breast cancer cell lines containing HER-2 gene amplification and high levels of HER-2 overexpression (>200 ng/mg protein), such as BT474, UACC812, SUM190, SK-BR-3, SUM225, UACC893, and MDA-MB-361, show IC50s less than 1 μM (ranging 10-900 nM), whereas those cell lines with HER-2 gene amplification but lower levels of HER-2 overexpression (100-200 ng/mg protein), such as EFM192A and MDA-MB-453, show IC50s equal to 1.1 and 3.9 μM, respectively. Furthermore, exposure of SK-BR-3 and BT474 human breast cancer cells to lapatinib result in a dose-dependent (lapatinib, 0.2-20 μM for 1 hour) and time-dependent (lapatinib, 10-60 minutes with 2 μM or 0.2 μM ) reduction of phosphorylation of EGFR, HER-2, AKT, and ERK. [2] Lapatinib (1 μM, dissolved in DMSO) inhibits steady-state phosphorylated ErbB2 (p-ErbB2) and p-Akt (S473) protein levels within 30 min but not in response to trastuzumab in BT474 and Au565 cells (two ErbB2-overexpressing breast cancer cell lines that are sensitive to the proapoptotic effects of lapatinib).[3] More than 90% of cells are viable at concentrations of lapatinib (diluted with medium) up to 2.5 μM in MCF-7 (human breast carcinoma cell line), MCF-7/adr (doxorubicin-selected derivative ABCB1-overexpressing MCF-7) , S1 (colon carcinoma cell line), and S1-M1-80 (mitoxantrone-selected derivative ABCG2-overexpressing S1) cells and lapatinib at 10 μM has virtually no cytotoxic effects on HEK293 cells when using the MTT assay.[4] In combination with tamoxifen, lapatinib (100 mg/kg daily by oral gavage) significantly inhibits the growth of tamoxifen-resistant ErbB2 over-expressing MCF-7 mammary tumor xenografts in ovariectomized athymic BALB/c nude mice.[5] Tumor growth is reduced by more than 57% (on average) compared to controls (433 mm3 versus 1015 mm3) after 4 weeks of daily treatment of A549 tumor-bearing mice with lapatinib (100 mg/kg body weight, daily gavage). Furthermore, lapatinib (100 mg/kg body weight, daily gavage) dramatically reduces tumor angiogenesis (vessel density estimated by analyzing CD31-stained tumor sections ) compared to controls (0.59 for lapatinib versus 4.6 for controls. Lapatinib also reveals that lapatinib treatment (150 mg/kg daily) strongly inhibits the tumor growth of (mouse embryonic fibroblasts) MEFs expressing 611-CTF (the most active fragment of p95 HER2).[7] |
