Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth

Abstract

ErbB2 is a ligand-less member of the ErbB receptor family that functions as a coreceptor with EGFR, ErbB3, and ErbB4. Here, we describe an approach to target ErbB2's role as a coreceptor using a monoclonal antibody, 2C4, which sterically hinders ErbB2's recruitment into ErbB ligand complexes. Inhibition of ligand-dependent ErbB2 signaling by 2C4 occurs in both low- and high-ErbB2-expressing systems. Since the ErbB3 receptor contains an inactive tyrosine kinase domain, 2C4 is very effective in blocking heregulin-mediated ErbB3-ErbB2 signaling. We demonstrate that the in vitro and in vivo growth of several breast and prostate tumor models is inhibited by 2C4 treatment.

Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms

“…The anti-ErbB1 antibody cetuximab inhibits ligandmediated phosphorylation of ErbB1 by directly competing with ligand binding to ErbB1 (Prewett et al, 1998). The anti-ErbB2 mAb pertuzumab sterically hinders recruitment of ErbB2 into ErbB/ligand complexes An isoform-specific anti-ErbB4 antibody M Hollmén et al affecting the formation and activation of ErbB2-containing dimers (Agus et al, 2002;Franklin et al, 2004). However, our preliminary in vitro experiments with recombinant proteins suggest that mAb 1479 does not compete with NRG binding to ErbB4 or interfere with NRG-induced ErbB4 dimerization.…”

Epidermal growth factor receptor dimerization status determines skin toxicity to HER-kinase targeted therapies

“…Blots were reprobed for b-actin to account for loading differences. (Agus et al, 2002;Mendoza et al, 2002) and further implies that NHEK lack the formation of such heterodimers in response to EGF.…”

“…PCR reactions for each template were run in triplicate using 1 mg of total RNA per sample. The sequences of the primer/ probe sets for the HER-kinase axis were described previously (Agus et al, 2002). Standard curves were constructed for each genespecific primer pair using 10 -1000 ng of total RNA prepared from CWR22R xenografts.…”

“…Pertuzumab is a HER2-specific humanized monoclonal antibody, which inhibits ligand-mediated intracellular signaling by blocking functional HER2 heterodimerization (Agus et al, 2002;Mendoza et al, 2002). Pertuzumab has a favorable toxicity profile and demonstrated clinical activity in a Phase I clinical trial in patients with advanced solid cancers (Agus et al, 2005b).…”

Targeting the function of the HER2 oncogene in human cancer therapeutics

“…But convincing evidence in support of this hypothesis has not yet emerged. In pulldown assays, trastuzumab does not inhibit HER2-HER3 interaction (Agus et al, 2002), and in fluorescence resonance energy transfer (FRET)-based assays trastuzumab also does not inhibit HER2 interaction with EGFR or HER3 (Diermeier et al, 2005). In a different model using truncated HER proteins fusing them to b-galactosidase fragments in an enzyme complementation assay, trastuzumab was reported to inhibit EGFR-HER2 interaction but not HER2-HER3 interactions (Wehrman et al, 2006).…”