Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src
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Marco Perez1, Antonio Lucena-Cacace1, Luis Miguel Marín-Gómez1,2, Javier Padillo-Ruiz1,2, Maria Jose Robles-Frias3,4, Carmen Saez1,3, Rocio Garcia-Carbonero5,6, Amancio Carnero1
1Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain
2Department of General Surgery, Virgen del Rocío University Hospital, Seville, Spain
3Department of Pathology, Virgen del Rocío University Hospital, Seville, Spain
4Present address: HUVR-IBiS Biobank, Virgen del Rocío University Hospital, Seville, Spain
5Department of Medical Oncology, Virgen del Rocío University Hospital, Seville, Spain
6Present address: Department of Medical Oncology, 12 of October University Hospital, Madrid, Spain
Rocio Garcia-Carbonero, email: [email protected]
Amancio Carnero, email: [email protected]
Keywords: metastatic colorectal carcinoma, cancer treatment, biomarkers, Src kinase, pdx models
Received: February 08, 2016 Accepted: March 31, 2016 Published: April 20, 2016
Despite the development of new antineoplastic agents for the treatment of colorectal cancer (CRC), oxaliplatin and fluoropyrimidines remain the most commonly employed drugs for the treatment of both early and advanced disease. Intrinsic or acquired resistance is, however, an important limitation to pharmacological therapy, and the development of chemosensitization strategies constitute a major goal with important clinical implications. In the present work, we determined that high levels of activated Src kinase, measured as phospho-Src at the Tyr419 residue in CRC cell lines, can promote colorectal carcinoma cell resistance to oxaliplatin, but not to 5-fluorouracil (5FU), and that inhibition of this protein restores sensitivity to oxaliplatin. Similar results were observed with in vivo patient-derived xenograft (PDX) models that were orthotopically grown in murine livers. In PDX tumor lines derived from human CRC liver metastasis, dasatinib, a Src inhibitor, increases sensitivity to oxaliplatin only in tumors with high p-Src. However, dasatinib did not modify sensitivity to 5FU in any of the models. Our data suggest that chemoresistance induced by p-Src is specific to oxaliplatin, and that p-Src levels can be used to identify patients who may benefit from this combination therapy. These results are relevant for clinicians as they identify a novel biomarker of drug resistance that is suitable to pharmacological manipulation.
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