Antitumor activity of a dual epidermal growth factor receptor and ErbB2 kinase inhibitor MP-412 (AV-412) in mouse xenograft models |
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Authors: | Tsuyoshi Suzuki Akihiro Fujii Junichi Ohya Hideo Nakamura Fumiko Fujita Masako Koike Masahide Fujita |
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Institution: | Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama;;Experimental Cancer Chemotherapy Research Laboratories Co., Osaka;;Association for Anticancer Drug Search, Osaka, Japan |
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Abstract: | Although epidermal growth factor receptor (EGFR) kinase inhibitors are effective for the treatment of non-small cell lung cancer (NSCLC), the emergence of mutations resistant to these inhibitors, such as T790M, has become a clinical problem. Recently, ErbB2 mutations have also been identified in a small number of NSCLC patients. Therefore, novel therapies to overcome these mutations are desirable. We describe the antitumor activity of MP-412 (AV-412), a dual EGFR/ErbB2 kinase inhibitor, against three lung cancer models with EGFR and ErbB2 mutations and also against various human xenografts with overexpression of these receptors. MP-412 inhibited phosphorylation of EGFR and its downstream signaling in NCI-H1650 and NCI-H1975 cell lines, which harbor the E746-A750 deletion and L858R + T790M point mutations, respectively, in EGFR . MP-412 inhibited the growth of these cell lines in vitro and in vivo , whereas the precedent kinase inhibitors lapatinib, erlotinib, and gefitinib were ineffective against NCI-H1975 cells in vivo . Furthermore, MP-412 inhibited ErbB2 signaling in the NCI-H1781 cell line, which harbors the G776V,C insertion in ErbB2 , and correlated with its antiproliferation activity. When its antitumor spectrum was further explored in several cancer types overexpressing EGFR or ErbB2, MP-412 showed potent activity in KPL-4 and DU145 xenografts, in which lapatinib was ineffective. MP-412 also inhibited tumor models in which conventional chemotherapies were less effective. These results suggest that MP-412 is a potent dual inhibitor with the potential for treating solid cancers that overexpress EGFR or ErbB2, including NSCLC cells harboring mutations resistant to the first generation of kinase inhibitors. ( Cancer Sci 2009) |
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