Abstract Inflammatory breast cancer (IBC) is the most lethal form of locally advanced breast cancer and carries a guarded prognosis. IBC presents with a “lumpless” primary tumor, which rapidly infiltrates and forms tumor emboli within the dermal lymphatic vessels of the skin overlying the breast. It is clear from the recent research advancements that IBC is a unique entity, not only in its clinical presentation, disease progression and response to therapy but also in its molecular expression profile. Therefore, it is essential to carry out molecular expression studies in IBC compared to non-IBC as well as to pursue these differences to study their effects on IBC phenotype. Our laboratory has demonstrated that the platelet derived growth factor receptor alpha (PDGFRa) is significantly over expressed in IBC patient samples (between 15-36%) compared to non-IBC patient samples. Using multiple approaches we demonstrate the PDGFRα activation signature in IBC patient samples and cell lines. Our data demonstrates that PDGFRα is constitutively active and localized in the cytoplasm of IBC cells. Although the receptor is intracellular, PDGFRα signaling remains intact. Thus, PDGFRα is an attractive target for therapy. Here we show that a novel PDGFR inhibitor, crenolanib, which specifically targets active PDGFR, is able to significantly inhibit IBC tumor growth and progression. In nude mice, 200 mm3 orthotopic IBC tumors did not increase in size when the mice were treated with crenolanib. In contrast, mice treated with vehicle control demonstrated a 4-fold increase in tumor growth over the 2-week course of the experiment. In addition, by using a novel in vitro IBC emboli growth model, we demonstrate that crenolanib prevents IBC tumor emboli formation and acts to sensitize IBC cells to chemotherapeutic agents. We were able to achieve a similar level of IBC cell killing with a 10-fold lower dose of chemotherapeutic agents compared to the agents by themselves. Together, these data demonstrate that PDGFRα is a viable target in IBC patients and that crenolanib is a potent and effective therapeutic agent against IBC cells. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-15.