Artículo
Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src.
Autor/es | Perez, Marco
Lucena Cacace, Antonio Marín Gómez, Luis Miguel Padillo Ruiz, Francisco Javier Robles Frias, MJ Saez, Carmen García Carbonero, Rocío Carnero Moya, Amancio |
Departamento | Universidad de Sevilla. Departamento de Cirugía Universidad de Sevilla. Departamento de Medicina |
Fecha de publicación | 2016-04-20 |
Fecha de depósito | 2020-04-29 |
Publicado en |
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Resumen | 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 ... 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. |
Cita | Perez, M., Lucena Cacace, A., Marín Gómez, L.M., Padillo Ruiz, F.J., Robles Frias, M., Saez, C.,...,Carnero Moya, A. (2016). Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src.. Oncotarget, 7 (22), 33111-33124. |
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