Characterization and Targeting of Platelet-Derived Growth Factor Receptor alpha (PDGFRA) in Inflammatory Breast Cancer (IBC)

Publication date: July 2017
Source:Neoplasia, Volume 19, Issue 7
Author(s): Madhura Joglekar-Javadekar, Steven Van Laere, Michael Bourne, Manal Moalwi, Pascal Finetti, Peter B. Vermeulen, Daniel Birnbaum, Luc Y. Dirix, Naoto Ueno, Monique Carter, Justin Rains, Abhijit Ramachandran, Francois Bertucci, Kenneth L. van Golen
PURPOSE: Inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer due to its rapid onset and highly invasive nature. IBC carries 5- and 10-year disease-free survival rates of ~45% and <20%, respectively. Multiple studies demonstrate that in comparison with conventional breast cancer, IBC has a unique molecular identity. Here, we have identified platelet-derived growth factor receptor alpha (PDGFRA) as being uniquely expressed and active in IBC patient tumor cells. EXPERIMENTAL DESIGN: Here we focus on characterizing and targeting PDGFRA in IBC. Using gene expression, we analyzed IBC patient samples and compared them with non-IBC patient samples. Further, using IBC cells in culture, we determined the effect of small molecules inhibitors in both in vitro and in vivo assays. RESULTS: In IBC patients, we show more frequent PDGFRA activation signature than non-IBC samples. In addition, the PDGFRA activation signature is associated with shorter metastasis-free survival in both uni- and multivariate analyses. We also demonstrate that IBC cells express active PDGFRA. Finally, we show that PDGFRA targeting by crenolanib (CP-868-596), but not imatinib (STI571), two small molecule inhibitors, interferes with IBC cell growth and emboli formation in vitro and tumor growth in vivo. CONCLUSIONS: Our data suggest that PDGFRA may be a promising target for therapy in IBC.



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