2C4, a monoclonal antibody against HER2, disrupts the HER kinase signaling pathway and inhibits ovarian carcinoma cell growth.
BACKGROUND
Human epidermal growth factor receptor 2 (HER2) is overexpressed in 25-30% of ovarian carcinoma cases and a correlation between increased HER2 expression and decreased survival has been demonstrated. HER2 is a ligand-less member of the HER family that functions as the preferred coreceptor for epidermal growth factor receptor (EGFR), HER3, and HER4.


METHODS
An approach was developed to target HER2's role as a coreceptor using a monoclonal antibody, 2C4, which sterically hinders HER2's recruitment into a functional HER complex.


RESULTS
HER2 was robustly expressed in all eight ovarian carcinoma cell lines; expression of EGFR and HER3 was variable. Even though four of the eight cell lines responded to EGF, 2C4 antibody moderately inhibited in vitro proliferation of only two cell lines (OVCA433 and SK-OV-3). Furthermore, ligand-stimulated p-MAPK expression was inhibited by 2C4 only in these two cell lines after exposure to EGF. Immunoprecipitation and eTag analysis revealed that OVCA433 expressed heterodimers of EGFR/HER2, and these heterodimers were disrupted after treatment with 2C4, whereas OVCA432 cells did not have these heterodimers. In murine xenograft experiments, the in vivo growth of OVCA433, but not of OVCA432, ovarian carcinoma cells was significantly inhibited by 2C4 treatment of the mice.


CONCLUSIONS
2C4 is able to disrupt the HER signaling pathway and inhibit the in vitro and in vivo growth of ovarian carcinoma cell lines. The response appears limited to lines in which HER2 heterodimers were able to transduce proliferative signals. Our findings suggest a strong rationale to conduct clinical trials of 2C4 in a subset of patients with ovarian tumors.
Takai
Noriyuki
N
Division of Hematology/Oncology, Cedars-Sinai Medical Center/UCLA School of Medicine, Los Angeles, CA 90048, USA.
Jain
Anjali
A
Kawamata
Norihiko
N
Popoviciu
Laura M
LM
Said
Jonathan W
JW
Whittaker
Sadie
S
Miyakawa
Isao
I
Agus
David B
DB
Koeffler
H Phillip
HP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism*; D012494:Sampling Studies; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D066246:ErbB Receptors; D006131:Growth Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; C481039:2C4 antibody