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Ref Type Journal Article
PMID (19459856)
Authors Suzuki T, Fujii A, Ohya J, Nakamura H, Fujita F, Koike M, Fujita M
Title Antitumor activity of a dual epidermal growth factor receptor and ErbB2 kinase inhibitor MP-412 (AV-412) in mouse xenograft models.
Journal Cancer science
Vol 100
Issue 8
Date 2009 Aug
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
AV-412 MP-412 EGFR Inhibitor (Pan) 46 EGFR Inhibitor 2nd gen 3 HER2 Inhibitor 23 AV-412 binds and inhibits EGFR and ERBB2 (HER2), which may result in the inhibition of tumor growth and angiogenesis in EGFR/HER2-expressing tumors (PMID: 17888033, PMID: 19459856).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 mutant lung non-small cell carcinoma sensitive AV-412 Preclinical Actionable In a preclinical study, non-small cell lung cancer cells harboring an ERBB2 (HER2) mutation demonstrated sensitivity to AV-412, resulting in decreased phosphorylation of Erbb2, Akt, and Erk (PMID: 19459856). 19459856