An ErbB3 Antibody, MM-121, Is Active in Cancers with Ligand-Dependent Activation

Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts, USA.
Cancer Research (Impact Factor: 9.28). 03/2010; 70(6):2485-94. DOI: 10.1158/0008-5472.CAN-09-3145
Source: PubMed

ABSTRACT ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in epidermal growth factor receptor (EGFR; ErbB1), ErbB2 [human epidermal growth factor receptor 2 (HER2)], and [hepatocyte growth factor receptor (MET)] addicted cancers, and reactivation of ErbB3 is a prominent method for cancers to become resistant to ErbB inhibitors. In this study, we evaluated the in vivo efficacy of a therapeutic anti-ErbB3 antibody, MM-121. We found that MM-121 effectively blocked ligand-dependent activation of ErbB3 induced by either EGFR, HER2, or MET. Assessment of several cancer cell lines revealed that MM-121 reduced basal ErbB3 phosphorylation most effectively in cancers possessing ligand-dependent activation of ErbB3. In those cancers, MM-121 treatment led to decreased ErbB3 phosphorylation and, in some instances, decreased ErbB3 expression. The efficacy of single-agent MM-121 was also examined in xenograft models. A machine learning algorithm found that MM-121 was most effective against xenografts with evidence of ligand-dependent activation of ErbB3. We subsequently investigated whether MM-121 treatment could abrogate resistance to anti-EGFR therapies by preventing reactivation of ErbB3. We observed that an EGFR mutant lung cancer cell line (HCC827), made resistant to gefitinib by exogenous heregulin, was resensitized by MM-121. In addition, we found that a de novo lung cancer mouse model induced by EGFR T790M-L858R rapidly became resistant to cetuximab. Resistance was associated with an increase in heregulin expression and ErbB3 activation. However, concomitant cetuximab treatment with MM-121 blocked reactivation of ErbB3 and resulted in a sustained and durable response. Thus, these results suggest that targeting ErbB3 with MM-121 can be an effective therapeutic strategy for cancers with ligand-dependent activation of ErbB3.

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Available from: Matthew Onsum, Feb 04, 2014
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    • "One case where a kinetic modelling approach has proved to be productive is in identifying novel anti-cancer drug targets (Schoeberl et al., 2009), based on the results of local sensitivity analysis. This led to the design of a novel drug candidate MM-121, which is a human monoclonal antibody that targets ErbB3 (Schoeberl et al., 2010). In our recent studies (Faratian et al., 2009b; Goltsov et al., 2011) we applied computational modelling methods, based on elucidation of control parameters within the PI3K/PTEN/Akt signalling module, to explore the mechanisms of therapeutic resistance to anti-ErbB2 inhibitors in human ovarian carcinoma cell lines. "
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