Lapatinib

Lapatinib is a potent purified EGFR and ErbB-2 inhibitor with IC50 of 10.2 and 9.8 nM, respectively. Lapatinib is >300-fold selective for EGFR and ErbB-2 over other kinases tested such as c-Src, MEK and ERK, except for ErbB-4. Lapatinib prevents receptor autophosphorylation of EGFR and ErbB-2 in a dose-responsive manner with IC50 of 0.17 and  0.08 μM against BT474 and HN5 cell lines, respectively.  The ability of Lapatinib to blocks EGFR and ErbB-2 autophosphorylation in EGFR- and ErbB-2-overexpressing tumor cells is ∼10-fold less than its potency on the purified enzyme. The ErbB-2-transfected mammary epithelial cell line, HB4a c5.2, is ∼40-fold more responsive to Lapatinib treatment than the untransfected parental control line, HB4a. Transient exposure to 30 μM Lapatinib results in complete inhibition of outgrowth of the HN5 cell population after ∼2 additional weeks of culture without Lapatinib. Lapatinib inhibits tumor growth by 50% occurs at concentrations of >3.3 μM. Significant prevention of outgrowth (20%) occurs at doses as low as 0.37 μM. Lapatinib is similar to OSI-774 in its ability to inhibit outgrowth of the EGFR-overexpressing cell line. Lapatinib is potent at inhibiting the growth of BT474 and HN5 human tumor xenografts. A dose-responsive inhibition of both models occurs on treatment of tumor-bearing mice with 30 and 100 mg/kg Lapatinib orally, twice daily. Lapatinib at the dose of the 100 mg/kg completely inhibits the growth of tumor. At this dose, there is