The effects of targeting stromal and tumor cell platelet-derived growth factor receptor (PDGFR) in non-small cell lung cancer (NSCLC).

Abstract

10533 Background: Platelet-derived growth factor receptor (PDGFR) has emerged as a potential target for cancer therapy. In non-small cell lung cancer (NSCLC), PDGFR is expressed frequently by stromal cells in the tumor microenvironment and, in a subset of tumors, by cancer cells themselves. However, most recent research has focused exclusively on cancer cell PDGFR, overlooking the effect of PDGFR inhibition in the tumor stroma. Methods: To evaluate the effects of targeting stromal PDGFR, which has roles in fibroblast activation, local tissue invasion, modulation of tumor interstitial pressure, and angiogenesis, we capitalized on the xenograft model and the availability of species-specific anti-PDGFRα antibodies. In this model, IMC 3G3, a fully human anti-human PDGFRα monoclonal antibody, inhibits cancer cell PDGFRα; IMC 1E10, a fully human anti-mouse PDGFRα monoclonal antibody, inhibits stromal PDGFRα. Results: We confirmed species specificity of IMC 3G3 and IMC 1E10 via (1) patterns of immunoreactivity with human PDGFR-positive cancer cells and mouse PDGFR-positive fibroblasts, (2) inhibition of murine fibroblast PDGFRα activation by IMC 1E10 but not by IMC 3G3, and (3) in vitro inhibition of proliferation of human PDGFR-positive cancer cells by IMC 3G3 but not by IMC 1E10. As expected, only rare NSCLC featuring high-level PDGFRα expression responded to inhibition of cancer cell PDGFRα. However, in vivo, stromal PDGFRα targeting inhibited the growth of PDGFRα-negative NSCLC xenografts and enhanced the effect of chemotherapy. Conclusions: IMC 3G3 and IMC 1E10 exhibit species-specific PDGFR targeting, allowing individual evaluation of tumor- and stromal PDGFRa inhibition. Stromal PDGFR inhibition may represent a means for enhancing control of lung cancer growth in some patients, independent of tumor cell PDGFR expression. Because PDGFR is widely expressed in NSCLC stromal cells, these findings suggest that stromal PDGFR inhibition could benefit a large proportion of these patients.