Preclinical Development Stromal Platelet-Derived Growth Factor Receptor a (PDGFRa) Provides a Therapeutic Target Independent of Tumor Cell PDGFRa Expression in Lung Cancer Xenografts

In lung cancer, platelet-derived growth factor receptor a (PDGFRa) is expressed frequently by tumorassociated stromal cells and by cancer cells in a subset of tumors.We sought to determine the effect of targeting stromal PDGFRa in preclinical lung tumor xenograft models (human tumor, mouse stroma). Effects of antihuman (IMC-3G3) and anti-mouse (1E10) PDGFRa monoclonal antibodies (mAb) on proliferation and PDGFRa signaling were evaluated in lung cancer cell lines and mouse fibroblasts. Therapy studies were conducted using established PDGFRa-positive H1703 cells and PDGFRa-negative Calu-6, H1993, and A549 subcutaneous tumors in immunocompromisedmice treatedwith vehicle, anti-PDGFRamAbs, chemotherapy, or combination therapy. Tumors were analyzed for growth and levels of growth factors. IMC-3G3 inhibited PDGFRa activation and the growth of H1703 cells in vitro and tumor growth in vivo, but had no effect on PDGFRa-negative cell lines or mouse fibroblasts. 1E10 inhibited growth and PDGFRa activation of mouse fibroblasts, but had no effect on human cancer cell lines in vitro. In vivo, 1E10-targeted inhibition of murine PDGFRa reduced tumor growth as single-agent therapy in Calu-6 cells and enhanced the effect of chemotherapy in xenografts derived fromA549 cells. We also identified that low expression cancer cell expression of VEGF-A and elevated expression of PDGF-AA were associated with response to stromal PDGFRa targeting. We conclude that stromal PDGFRa inhibition represents a means for enhancing control of lung cancer growth in some cases, independent of tumor cell PDGFRa expression.Mol Cancer Ther; 11(11); 2473–82. 2012 AACR.