MP-412, a dual EGFR/HER2 tyrosine kinase inhibitor shows antitumor activity against both Erlotinib/Gefitinib-sensitive and resistant EGFR mutations in human lung cancer xenograft models

Proc Amer Assoc Cancer Res, Volume 47, 2006 4030 EGFR and HER2 in tumor cells are well-validated target molecules in cancer treatment. Inhibition of EGFR by gefitinib (Iressa) is demonstrated to bring clinical benefit in cancer chemotherapy. However, recent progress suggests that the T790M acquired mutation occurred in EGFR kinase domain of human lung cancer render resistance against gefitinib and erlotinib (Tarceva), another EGFR-directed agent. In previous study, MP-412, a new dual EGFR/HER2 tyrosine kinase inhibitor of an anilinoquinazoline class of compound showed a potent antitumor activity against various EGFR/HER2 expressing and gefitinib-resistant human tumors in xenograft models (Abstracts #3394 and 3405, AACR 2005). To assess antitumor activity of MP-412 against human tumors with this acquired mutation in EGFR, we examined its effects on 2 established NSCLC cell lines, gefitinib-sensitive H1650 containing deletion E746-A750 mutation and H1975 containing L858R and T790M double mutations, refractory to gefitinib, implanted in nude mice. When administrated orally, MP-412 (75 and 150 mg/kg) significantly suppressed tumor growth of H1975, whereas gefitinib (113 and 225 mg/kg) and erlotinib (100 mg/kg) showed no clear effects against this cell line. In the case of H1650, all 3 agents clearly inhibited the growth of tumor at same doses. When compared the inhibitory activity of these agents against in vitro autophosphorylation of EGFR and phosphorylation of its downstream signaling molecules, AKT and MAPK of both NSCLC cells stimulated with EGF, MP-412 suppressed both EGFR autophosphorylation and phosphorylation of AKT and MAPK in 2 cell lines at the concentration of 0.1 micro mol/L or higher. In contrast, inhibitory effects of gefitinib and erlotinib against AKT and MAPK phosphorylation in H1975 cells were weak at up to 10 micro mol/L. These suggest that MP-412 may have an interesting characteristic in antitumor activity against human lung cancer containing an acquired gefitinib-resistant EGFR mutation. It is expected that MP-412 would be a therapeutic agent of cancer patients, including those refractory to gefitinib and erlotinib.