Lapatinib

With the exception of ErbB-4, Lapatinib is >300-fold selective for EGFR and ErbB-2 over other kinases tested including c-Src, MEK and ERK. Treatment with Lapatinib inhibits 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 inhibit EGFR and ErbB-2 autophosphorylation in EGFR- and ErbB-2-overexpressing tumor cells is ∼10-fold less than its potency on the purified enzyme. Lapatinib inhibits the growth of both EGFR- and ErbB-2-overexpressing cells, whereas OSI-774 and Iressa which are EGFR selective inhibitors preferentially inhibit the growth of the EGFR-overexpressing cell lines. Lapatinib is ∼100-fold more potent on the tumor cell lines than on the normal fibroblast cells. 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. Inhibition of outgrowth by 50% occurs at concentrations >3.3 μM. Significant inhibition of outgrowth (20%) occurs at doses as low as 0.37 μM. Another EGFR-overexpressing cell line, A-431, responds similarly to HN5. Lapatinib is similar to OSI-774 in its ability to inhibit outgrowth of the EGFR-overexpressing cell line.