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IPGWAS: an integrated pipeline for rational quality control and association analysis of genome-wide genetic studies |
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| Authors: | Fan Yan-Hui Song You-Qiang |
| Affiliation: | a Pediatric Cancer Biology Program, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA b Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229, USA c Division of Pediatric Hematology and Oncology, Department of Pediatrics, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA d Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA e Department of Medicine, University of Texas Health Science Center, San Antonio, TX 78229, USA f Epidemiology and Biostatistics, University of Texas Health Science Center, San Antonio, TX 78229, USA g Department of Electrical Engineering, Texas Tech University, Lubbock, TX, USA h Department of Computer Engineering, Texas Tech University, Lubbock, TX, USA i Department of Anatomic Pathology, Cleveland Clinic, Taussig Cancer Center and the Lerner Research Institute, Cleveland, OH 44195, USA |
| Abstract: | Alveolar rhabdomyosarcoma (aRMS) is a very aggressive sarcoma of children and young adults. Our previous studies have shown that small molecule inhibition of Pdgfra is initially very effective in an aRMS mouse model. However, slowly evolving, acquired resistance to a narrow-spectrum kinase inhibitor (imatinib) was common. We identified Src family kinases (SFKs) to be potentiators of Pdgfra in murine aRMS primary cell cultures from mouse tumors with evolved resistance in vivo in comparison to untreated cultures. Treating the resistant primary cell cultures with a combination of Pdgfra and Src inhibitors had a strong additive effect on cell viability. In Pdgfra knockout tumors, however, the Src inhibitor had no effect on tumor cell viability. Sorafenib, whose targets include not only PDGFRA but also the Src downstream target Raf, was effective at inhibiting mouse and human tumor cell growth and halted progression of mouse aRMS tumors in vivo. These results suggest that an adaptive Src-Pdgfra-Raf-Mapk axis is relevant to PDGFRA inhibition in rhabdomyosarcoma. |
| Keywords: | Imatinib Sorafenib Receptor tyrosine kinase Pdgfra |
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