Anti‐HER‐3 MAbs inhibit HER‐3‐mediated signaling in breast cancer cell lines resistant to anti‐HER‐2 antibodies

Horst, Edward Htun van der; Murgia, Marta; Treder, Martin; Ullrich, Axel

doi:10.1002/ijc.20867

Cited by 45 publications

(46 citation statements)

References 45 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Downregulation of membrane HER3 upon RG7116 treatment was consistently observed, further contributing to its inhibition of HER3 signaling in vitro and in vivo. HER3 downregulation by ligand-blocking antibodies has been reported before for a-HER3-ECD antibody (47) and in some cancer cell lines with MM-121 (48). The potent and complete blockage of HER3 activation by RG7116 resulted in substantial TGI in several mouse tumor xenograft models, including some complete remissions.…”

Section: Discussionmentioning

confidence: 64%

RG7116, a Therapeutic Antibody That Binds the Inactive HER3 Receptor and Is Optimized for Immune Effector Activation

et al. 2013

View full text Add to dashboard Cite

The EGF receptor (EGFR) HER3 is emerging as an attractive cancer therapeutic target due to its central position in the HER receptor signaling network. HER3 amplifies phosphoinositide 3-kinase (PI3K)-driven tumorigenesis and its upregulation in response to other anti-HER therapies has been implicated in resistance to them. Here, we report the development and characterization of RG7116, a novel anti-HER3 monoclonal antibody (mAb) designed to block HER3 activation, downregulate HER3, and mediate enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via glycoengineering of the Fc moiety. Biochemical studies and X-ray crystallography revealed that RG7116 bound potently and selectively to domain 1 of human HER3. Heregulin binding was prevented by RG7116 at concentrations more than 1 nmol/L as was nearly complete inhibition of HER3 heterodimerization and phosphorylation, thereby preventing downstream AKT phosphorylation. In vivo RG7116 treatment inhibited xenograft tumor growth up to 90% relative to controls in a manner accompanied by downregulation of cell surface HER3. RG7116 efficacy was further enhanced in combination with anti-EGFR (RG7160) or anti-HER2 (pertuzumab) mAbs. Furthermore, the ADCC potency of RG7116 was enhanced compared with the nonglycoengineered parental antibody, both in vitro and in orthotopic tumor xenograft models, where an increased median survival was documented. ADCC degree achieved in vitro correlated with HER3 expression levels on tumor cells. In summary, the combination of strong signaling inhibition and enhanced ADCC capability rendered RG7116 a highly potent HER3-targeting agent suitable for clinical development. Cancer Res; 73(16); 5183-94. Ó2013 AACR.

show abstract

Section: Discussionmentioning

confidence: 64%

RG7116, a Therapeutic Antibody That Binds the Inactive HER3 Receptor and Is Optimized for Immune Effector Activation

et al. 2013

View full text Add to dashboard Cite

show abstract

“…209,[225][226][227] In ERBB2-over-expressing breast tumor cells, G1 progression after NRG stimulation was associated with ERBB2 transactivation of ERBB3 and stimulation of the PI3K pathway. 228 Contributions of ERBB3 and/or the ERBB2/ ERBB3 complex to these phenotypic effects of NRG has been confirmed by use of anti-ERBB2 or anti-ERBB3 antibodies 211,212,229 or of a dominant-negative ERBB3 construct. 230 The downstream participation of PI3K or pAKT was confirmed in some of these studies by use of pharmacological or dominant-negative inhibitors of PI3K 209 or by constitutively active constructs of the p110 catalytic subunit of PI3K and by pharmacological inhibition of AKT.…”

Section: Erbb3 In Normal and Neoplastic Tissues Cell Transformation Bmentioning

confidence: 88%

The ERBB3 receptor in cancer and cancer gene therapy

2008

View full text Add to dashboard Cite

ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

show abstract

“…HER3 had not been regarded as a treatment target in the view of the inactive tyrosine kinase function. However, an antibody directed against HER3 inhibited HER3-mediated signaling pathways in breast cancer cells even in cancer cells resistant to HER2 (56). A recent study of gastric cancer cells showed that HER family kinases were targets of amplified fibroblast growth factor receptor 2, and inhibition of HER3 resulted in a loss of cell proliferation introduced by fibroblast growth factor receptor 2 (57).…”

Section: Discussionmentioning

confidence: 99%

High Expression of HER3 Is Associated with a Decreased Survival in Gastric Cancer

Hayashi

Inokuchi

Takagi

et al. 2008

Clinical Cancer Research

123

102

View full text Add to dashboard Cite

Background: The role of human epidermal growth factor receptor (HER) 3 and HER4 has been elucidated in gastric cancer. HER1 and HER2 overexpression are regarded as prognostic factors and targets of treatment. The dimerization of the HER family receptors activates downstream signal pathways and promotes tumor progression. This study investigated the positive correlation between HER1and HER4 expression and the prognosis of patients with gastric cancers. Experimental Design: Tumor samples were obtained from gastric adenocarcinomas of 134 patients who underwent a gastrectomy from 1999 to 2002. The expression of each HER was analyzed in the tumor by immunohistochemical staining. Parametric correlations were done between HER expression and the clinicopathologic findings. A multivariate analysis was done with the overall survival. Results: HER3 expression was significantly associated with parameters involved with tumor progression, including the depth of tumor invasion (T 1 versusT 2 -T 4 ; P = 0.000), involved lymph nodes (P = 0.000), distant metastasis (P = 0.008), tumor stage (P = 0.000), and recurrent disease (P = 0.000). HER1was also significantly associated with those factors excluding distant metastasis. A significant relationship was observed between the expression of HER1 and HER3 (P = 0.000). HER3 overexpression was associated with a significantly worse survival (P = 0.0000) and was an independent prognostic factor in the multivariate analysis (hazard ratio, 2.382; 95% confidence interval, 1.009-5.625; P = 0.048). Conclusions: HER3 overexpression is strongly associated with tumor progression and poor prognosis of patients with gastric cancer. It may become a new prognostic factor and a target of treatment.

show abstract

Anti‐HER‐3 MAbs inhibit HER‐3‐mediated signaling in breast cancer cell lines resistant to anti‐HER‐2 antibodies

Cited by 45 publications

References 45 publications

RG7116, a Therapeutic Antibody That Binds the Inactive HER3 Receptor and Is Optimized for Immune Effector Activation

RG7116, a Therapeutic Antibody That Binds the Inactive HER3 Receptor and Is Optimized for Immune Effector Activation

The ERBB3 receptor in cancer and cancer gene therapy

High Expression of HER3 Is Associated with a Decreased Survival in Gastric Cancer

Contact Info

Product

Resources

About