Constitutive activation of EGFR is associated with tumor progression and plays a prominent role in malignant phenotype of chondrosarcoma
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Jun Qin1, Irfan Shaukat1, Didier Mainard1, Patrick Netter1, Lydia Barré1 and Mohamed Ouzzine1
1 UMR7365 Centre National de la Recherche Scientifique (CNRS), Université de Lorraine, Biopôle, Faculty of Medicine, Nancy 54505, France
Keywords: chondrosarcoma; EGF/EGFR signaling; biomarker; tyrosine kinase inhibitor; cell death
Received: October 02, 2018 Accepted: April 14, 2019 Published: May 07, 2019
Chondrosarcoma is a highly agressive cancer with currently no effective therapies when unresectable or metastasized, thus the outcome remains poor. High-grade chordrosarcomas are resistant to conventional chemotherapy and radiotherapy and surgical resection remains the only treatment for the majority of chondrosarcomas. Constitutive activation of receptor tyrosine kinases has been shown to be important for malignant transformation and tumour proliferation. Here, we investigated the activation status of EGFR in chondrosarcoma tumor biopsies and cell lines. We found that EGFR is activated in grade II and grade III chondrosarcoma tumors but not in grade I tumors, suggesting a role in tumor progression. Interestingly, we showed that EGFR is activated through an autocrine loop and that inhibition of the EGFR by the TKI, tyrphostin AG1478 or EGFR neutralizing antibodies strongly reduced activation of oncogenic ERK1/2 and mTOR/AKT downstream pathways. Importantly, inhibition of EGFR profoundly reduces cell proliferation and migration, inhibits the expression of MMP13 and MMP3 and enhances cell death. Taken together, these data support the blocking of EGFR as new potential treatment for high-grade chondrosarcoma tumors.
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