Therapeutic IMC-C225 antibody inhibits breast cancer cell invasiveness via Vav2-dependent activation of RhoA GTPase.
OBJECTIVE
Abnormalities in the expression and signaling pathways downstream of epidermal growth factor receptor (EGFR) contribute to progression, invasion, and maintenance of the malignant phenotype in human cancers. Accordingly, biological agents, such as the EGFR-blocking antibody IMC-C225 have promising anticancer potential and are currently in various stages of clinical development. Because use of IMC-C225 is limited, at present, only for treatment of cancer with high EGFR expression, the goal of the present study was to determine the effect of IMC-C225 on the invasiveness of breast cancer cells with high and low levels of EGFR expression.


METHODS
The effect of IMC-C225 on invasion was studied using breast cancer cell lines with high and low levels of EGFR expression.


RESULTS
The addition of EGF led to progressive stress fiber dissolution. In contrast, cells treated with IMC-C225 showed reduced invasiveness and increased stress-fiber formation. Interestingly, IMC-C225 pretreatment was accompanied by EGFR phosphorylation, as detected using an anti-phosphorylated tyrosine antibody (PY99), which correlated with phosphorylation of Vav2 guanine nucleotide exchange factor and activation of RhoA GTPase irrespective of EGFR level, and Vav2 interacted with EGFR only in IMC-C225-treated cells. The underlying mechanism involved an enhanced interaction between beta1 integrins and EGFR upon IMC-C225 treatment.


CONCLUSIONS
Here, we defined a new mechanism for IMC-C225 that cross-links integrins with EGFR, leading to activation of RhoA and inhibition of breast cancer cell invasion irrespective of the level of EGFR in the cells, thus providing a rationale for using IMC-C225 in the metastatic setting independent of the levels of EGFR.
Molli
Poonam R
PR
Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Adam
Liana
L
Kumar
Rakesh
R
D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000276:immunology* / Q000473:pathology*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003599:Cytoskeleton / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010641:Phenotype; D010766:Phosphorylation; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism* / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000737:chemistry*; D020742:rhoA GTP-Binding Protein / Q000737:chemistry* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D051567:Proto-Oncogene Proteins c-vav; C093651:VAV2 protein, human; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000068818:Cetuximab