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

Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts, USA.
Cancer Research (Impact Factor: 9.33). 03/2010; 70(6):2485-94. DOI: 10.1158/0008-5472.CAN-09-3145
Source: PubMed


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.

Download full-text


Available from: Matthew Onsum, Feb 04, 2014
36 Reads
  • Source
    • "However, a principal challenge to target erbB3 is that, unlike other erbB family members, the erbB3 receptor lacks or possesses much lower intrinsic kinase activity [10,11], suggesting that its function cannot be inhibited by a small molecule inhibitor (Figure 2). Thus, targeting of erbB3 with a blocking Ab is the only strategy currently under preclinical investigation [22,23] and clinical evaluation in patients with advanced solid tumors ( Recent studies have identified bispecific Abs dual-targeting of EGFR/erbB3 [21] or erbB2/erbB3 [25], that exert potent antitumor activities in laboratory research and are now in clinical testing [86]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The erbB receptors, including the epidermal growth factor receptor (EGFR), erbB2 (also known as HER2/neu), erbB3 (or HER3), and erbB4 (or HER4), are often aberrantly activated in a wide variety of human cancers. They are excellent targets for selective anti-cancer therapies because of their transmembrane location and pro-oncogenic activity. While several therapeutic agents against erbB2 and/or EGFR have been used in the treatment of human cancers with efficacy, there has been relatively less emphasis on erbB3 as a molecular target. Elevated expression of erbB3 is frequently observed in various malignancies, where it promotes tumor progression via interactions with other receptor tyrosine kinases (RTKs) due to its lack of or weak intrinsic kinase activity. Studies on the underlying mechanisms implicate erbB3 as a major cause of treatment failure in cancer therapy, mainly through activation of the PI-3 K/Akt, MEK/MAPK, and Jak/Stat signaling pathways as well as Src kinase. It is believed that inhibition of erbB3 signaling may be required to overcome therapeutic resistance and effectively treat cancers. To date, no erbB3-targeted therapy has been approved for cancer treatment. Targeting of erbB3 receptor with a monoclonal antibody (Ab) is the only strategy currently under preclinical study and clinical evaluation. In this review, we focus on the role of erbB3-initiated signaling in the development of cancer drug resistance and discuss the latest advances in identifying therapeutic strategies inactivating erbB3 to overcome the resistance and enhance efficacy of cancer therapeutics.
    Molecular Cancer 05/2014; 13(1):105. DOI:10.1186/1476-4598-13-105 · 4.26 Impact Factor
  • Source
    • "In a subset of EGFR mutant lung cancers, amplification of HER2, presumably involving HER3 reactivation, was also identified as a resistance mechanism to EGFR TKIs (Takezawa et al., 2012). Consistent with these data, blockade of HER3 with the neutralizing antibody MM-121 increases the efficacy of cetuximab in a mouse model of EGFR mutant lung cancer (Schoeberl et al., 2010). Along those lines, a selective ADAM inhibitor, INCB3619, which prevents the processing and activation of multiple ERBB ligands including heregulin, inhibits HER3 signaling and enhances gefitinib-mediated inhibition of EGFR in NSCLC (Zhou et al., 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: ERBB receptors were linked to human cancer pathogenesis approximately three decades ago. Biomedical investigators have since developed substantial understanding of the biology underlying the dependence of cancers on aberrant ERBB receptor signaling. An array of cancer-associated genetic alterations in ERBB receptors has also been identified. These findings have led to the discovery and development of mechanism-based therapies targeting ERBB receptors that have improved outcome for many cancer patients. In this Perspective, we discuss current paradigms of targeting ERBB receptors with cancer therapeutics and our understanding of mechanisms of action and resistance to these drugs. As current strategies still have limitations, we also discuss challenges and opportunities that lie ahead as basic scientists and clinical investigators work toward more breakthroughs.
    Cancer cell 03/2014; 25(3):282-303. DOI:10.1016/j.ccr.2014.02.025 · 23.52 Impact Factor
  • Source
    • "It inhibits ligand-induced dimerization of erbB3 and erbB2 and subsequently inactivates the downstream signaling. MM-121 has been demonstrated to exert antitumor activity in preclinical models of human cancers, including erbB2+ breast cancer [18,19]. However, whether MM-121 holds potential to overcome trastuzumab resistance and enhance trastuzumab-mediated growth inhibition in erbB2+ breast cancer cells remains unclear. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. Our recent studies indicate that erbB3 interacts with both erbB2 and IGF-1 receptor to form a heterotrimeric complex in trastuzumab-resistant breast cancer cells. Herein, we investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab. MTS-based proliferation assays were used to determine cell viability upon treatment of trastuzumab and/or MM-121/SAR256212. Cell cycle progression was examined by flow cytometric analysis. Western blot analyses were performed to determine the expression and activation of proteins. Tumor xenografts were established by inoculation of the trastuzumab-resistant BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with trastuzumab and/or MM-121/SAR256212 via i.p injection to determine the Abs' antitumor activity. Immunohistochemical analyses were carried out to study the Abs' inhibitory effects on tumor cell proliferation and induction of apoptosis in vivo. MM-121 significantly enhanced trastuzumab-induced growth inhibition in two sensitive and two resistant breast cancer cell lines. MM-121 in combination with trastuzumab resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and Akt (P-Akt) in the in vitro studies. MM-121 combined with trastuzumab did not induce apoptosis in the trastuzumab-resistant cell lines under our cell culture condition, rather induced cell cycle G1 arrest mainly associated with the upregulation of p27kip1. Interestingly, in the tumor xenograft model established from the trastuzumab-resistant cells, MM-121 in combination with trastuzumab as compared to either agent alone dramatically inhibited tumor growth correlated with a significant reduction of Ki67 staining and increase of cleaved caspase-3 in the tumor tissues. The combination of MM-121 and trastuzumab not only inhibits erbB2-overexpressing breast cancer cell proliferation, but also promotes the otherwise trastuzumab-resistant cells undergoing apoptosis in an in vivo xenografts model. Thus, MM-121 exhibits potent antitumor activity when combined with trastuzumab under the studied conditions. Our data suggest that further studies regarding the suitability of MM-121 for treatment of breast cancer patients whose tumors overexpress erbB2 and become resistant to trastuzumab may be warranted.
    Molecular Cancer 11/2013; 12(1):134. DOI:10.1186/1476-4598-12-134 · 4.26 Impact Factor
Show more