Blockade of Epidermal Growth Factor- or Heregulin-Dependent ErbB2 Activation with the Anti-ErbB2 Monoclonal Antibody 2C4 Has Divergent Downstream Signaling and Growth Effects

Jackson, James G.; Clair, Patricia St.; Sliwkowski, Mark X.; Brattain, Michael G.

doi:10.1158/0008-5472.can-03-3106

Cited by 95 publications

(73 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Similarly, HRGh1 activation of these pathways in two prostate cancer lines was fully reversed (12). In GEO colon cancer cells, pertuzumab inhibited both EGF and HRGh1 stimulation of Akt but could only inhibit HRGh1 stimulation of ERK (13).…”

Section: Discussionmentioning

confidence: 87%

Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling

Mullen

Cameron

Hasmann

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Pertuzumab (Omnitarg, rhuMab 2C4) is a humanized monoclonal antibody, which inhibits HER2 dimerization. Because it has shown some clinical activity in ovarian cancer, this study sought to identify predictors of response to this agent in a model of ovarian cancer. A panel of 13 ovarian cancer cell lines was treated with heregulin B1 (HRGB1) or transforming growth factor-A, and cell proliferation was assessed. Both agents increased cell number in the majority of cell lines studied, the response to both being similar (r = 0.83; P = 0.0004, Pearson test). HRGB1 stimulation could be partially reversed by pertuzumab in 6 of 13 cell lines, with complete reversal in PE04 and PE06 cells. Addition of pertuzumab to transforming growth factor-AÀstimulated cells produced growth inhibition in 3 of 13 cell lines (PE01, PE04, and PE06). The magnitude of HRGB1-driven growth stimulation correlated significantly with an increase in extracellular signal-regulated kinase 2 (P = 0.037) but not Akt (P = 0.99) phosphorylation. Such HRGB1-driven phosphorylation of extracellular signalregulated kinase 1/2 and Akt could be reduced with pertuzumab, accompanied by changes in cell cycle distribution. In cell lines responsive to pertuzumab, HRGB1-enhanced phosphorylation of HER2 (Tyr 877 ) was reduced. Estrogenstimulated changes in growth, cell cycle distribution, and signaling were reversed by pertuzumab, indicating crosstalk between HER2 and estrogen signaling. These data indicate that there is a subset of ovarian cancer cell lines sensitive to pertuzumab and suggest possible predictors of response to identify patients who could benefit from this therapy. Furthermore, we have identified an interaction between HER2 and estrogen signaling in this disease.

show abstract

Section: Discussionmentioning

confidence: 87%

Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling

Mullen

Cameron

Hasmann

et al. 2007

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…This was attributed to pertuzumab's ability to inhibit liganddependent heterodimerisation and activation of downstream targets such as mitogen-activated protein kinase and Akt. In addition, pertuzumab was found to inhibit ligand-dependent activation and signalling in several other cell lines (Jackson et al, 2004;Takai et al, 2005). Although a synergistic effect on signal transduction inhibition in those cell lines is certainly conceivable, it is not entirely clear how both antibodies would have a potentiating effect on ADCC, particularly in cell lines that do not overexpress HER2/neu.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike trastuzumab (Herceptin), the principal mechanism of action of which is believed to be through recruiting host immune cells (natural killer (NK) cells) and setting off an antibody-dependent cell-mediated cytotoxicity (ADCC) process (Clynes et al, 2000;Gennari et al, 2004;Arnould et al, 2006), pertuzumab is believed to inhibit a wider array of downstream signal transduction pathways through inhibition of lateral signal transduction, that is, heterodimerisation. Several in vitro and in vivo studies conducted on a variety of human tumour cell lines have clearly elucidated this mechanism of action (Mullen et al, 2007;Agus et al, 2002;Jackson et al, 2004;Nahta et al, 2004;Takai et al, 2005). To our knowledge, however, a therapeutic potential for pertuzumab has, thus far, not been reported in endometrial cancer management.…”

mentioning

confidence: 98%

In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma

et al. 2009

View full text Add to dashboard Cite

BACKGROUND: Uterine serous papillary adenocarcinoma (USPC) is a rare but highly aggressive variant of endometrial cancer. Pertuzumab is a new humanised monoclonal antibody (mAb) targeting the epidermal growth factor type II receptor (HER2/neu). We evaluated pertuzumab activity separately or in combination with trastuzumab against primary USPC cell lines expressing different levels of HER2/neu. METHODS: Six USPC cell lines were assessed by immunohistochemistry (IHC), flow cytometry, and real-time PCR for HER2/neu expression. c-erbB2 gene amplification was evaluated using fluorescent in situ hybridisation (FISH). Sensitivity to pertuzumab and trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) was evaluated in 5 h chromium release assays. Pertuzumab cytostatic activity was evaluated using proliferation-based assays. RESULTS: Three USPC cell lines stained heavily for HER2/neu by IHC and showed amplification of the c-erbB2 gene by FISH. The remaining FISH-negative USPCs expressed HER2/neu at 0/1 þ levels. In cytotoxicity experiments against USPC with a high HER2/neu expression, pertuzumab and trastuzumab were similarly effective in inducing strong ADCC. The addition of complementcontaining plasma and interleukin-2 increased the cytotoxic effect induced by both mAbs. In low HER2/neu USPC expressors, trastuzumab was more potent than pertuzumab in inducing ADCC. Importantly, in this setting, the combination of pertuzumab with trastuzumab significantly increased the ADCC effect induced by trastuzumab alone (P ¼ 0.02). Finally, pertuzumab induced a significant inhibition in the proliferation of all USPC cell lines tested, regardless of their HER-2/neu expression. CONCLUSION: Pertuzumab and trastuzumab induce equally strong ADCC and CDC in FISH-positive USPC cell lines. Pertuzumab significantly increases tratuzumab-induced ADCC against USPC with a low HER2/neu expression and may represent a new therapeutic agent in patients harbouring advanced/recurrent and/or refractory USPC.

show abstract

“…Lysates (400 g of protein) were incubated with p85 antibody (Upstate) at 4°C overnight, followed by a further incubation with protein A-agarose for 2 h. Immune complexes were washed twice with each wash buffer (PI3K wash 1, phosphate-buffered saline, 1% Nonidet P-40/NaVO 4 ; PI3K wash 2, 100 mM Tris pH 7.4, 5 mM LiCl/NaVO 4 ; PI3K wash 3, 10 mM Tris, pH 7.4, 150 mM NaCl, 5 mM EDTA/NaVO 4 ). After the last wash was removed, PI 3-kinase assays were performed as described previously (44). Briefly, samples were resuspended in 50 l of PI3K buffer (20 mM Tris, pH 7.5, 100 mM NaCl, and 0.5 mM EGTA), and 10 g of phosphatidylinositol was added.…”

Section: Methodsmentioning

confidence: 99%

Knockdown of Ron Kinase Inhibits Mutant Phosphatidylinositol 3-Kinase and Reduces Metastasis in Human Colon Carcinoma

Wang

Rajput

Kan

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Abnormal accumulation and activation of receptor tyrosine kinase Ron (recepteur d'origine nantais) has been demonstrated in a variety of primary human cancers. We show that RNA interference-mediated knockdown of Ron kinase in a highly tumorigenic colon cancer cell line led to reduced proliferation as compared with the control cells. Decreased Ron expression sensitized HCT116 cells to growth factor deprivation stress-induced apoptosis as reflected by increased DNA fragmentation and caspase 3 activation. In addition, cell motility was decreased in Ron knockdown cells as measured by wound healing assays and transwell assays. HCT116 cells are heterozygous for gain of function mutant PIK3CA H1047R. Analysis of signaling proteins that are affected by Ron knockdown revealed that phosphatidylinositol 3-kinase (PI3K) activity of the mutant PI3K as well as AKT phosphorylation was substantially reduced in the Ron knockdown cells compared with the control cells. Moreover, we demonstrated in vivo that knockdown of Ron expression significantly reduced lung metastasis as compared with the control cells in the orthotopic models. In summary, our results demonstrate that Ron plays an essential role in maintaining malignant phenotypes of colon cancer cells through regulating mutant PI3K activity. Therefore, targeting Ron kinase could be a potential strategy for colon cancer treatment, especially in patients bearing gain of function mutant PI3K activity.The receptor tyrosine kinase Ron (recepteur d'origine nantais) belongs to the Met proto-oncogene family (1, 2). Mature Ron is a 180-kDa heterodimer composed of a 40-kDa extracellular ␣-chain and a 150-kDa transmembrane ␤-chain with tyrosine kinase activity (2). Macrophage-stimulating protein is the only ligand that has been identified for Ron (3, 4). Upon ligand binding, Ron dimerizes, becomes autophosphorylated, and transduces a variety of signals that regulate different downstream pathways including Ras/mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), 3 c-Jun N-terminal kinase (JNK), ␤-catenin, and nuclear factor-B (5-12). Ron can be activated through ligand-dependent or -independent mechanisms (3,13,14), which lead to responses important for tumorigenesis and metastasis, including cell scattering, proliferation, motility, and survival (15,16).Ron is normally expressed at relatively low levels in cells of epithelial origin (4). Recent studies have shown that Ron is overexpressed in 47% of breast tumor tissues as compared with benign epithelium and that elevated Ron expression was strongly associated with invasive activity by tumors (17). In addition, Ron is moderately expressed in normal colorectal mucosa, but is significantly increased in the majority of primary human colorectal adenocarcinoma samples (18). Ron overexpression has also been demonstrated in head and neck tumors (19). Furthermore, splice variants of Ron have been identified in human colon cancer. These variants were found to confer constitutive Ron activity, transformation, and tumorige...

show abstract

Blockade of Epidermal Growth Factor- or Heregulin-Dependent ErbB2 Activation with the Anti-ErbB2 Monoclonal Antibody 2C4 Has Divergent Downstream Signaling and Growth Effects

Cited by 95 publications

References 54 publications

Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling

Sensitivity to pertuzumab (2C4) in ovarian cancer models: cross-talk with estrogen receptor signaling

In vitro activity of pertuzumab in combination with trastuzumab in uterine serous papillary adenocarcinoma

Knockdown of Ron Kinase Inhibits Mutant Phosphatidylinositol 3-Kinase and Reduces Metastasis in Human Colon Carcinoma

Contact Info

Product

Resources

About