Luis Miguel Marín-Gómez, Javier Padillo-Ruiz, María José Robles-Frías, Amancio Carnero, Antonio Lucena-Cacace, Carmen Sáez, Rocio Garcia-Carbonero, Marco Perez, Junta de Andalucía, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Red Temática de Investigación Cooperativa en Cáncer (España), Universidad de Sevilla. Departamento de Cirugía, Universidad de Sevilla. Departamento de Medicina, Universidad de Sevilla. CTS664: Cirugía avanzada y trasplantes. Terapia celular y bioingeniería aplicada a la cirugía., [Perez, Marco] Univ Seville, CSIC, Inst Biomed Sevilla, IBIS,Hosp Univ Virgen del Rocio, Seville, Spain, [Lucena-Cacace, Antonio] Univ Seville, CSIC, Inst Biomed Sevilla, IBIS,Hosp Univ Virgen del Rocio, Seville, Spain, [Miguel Marin-Gomez, Luis] Univ Seville, CSIC, Inst Biomed Sevilla, IBIS,Hosp Univ Virgen del Rocio, Seville, Spain, [Padillo-Ruiz, Javier] Univ Seville, CSIC, Inst Biomed Sevilla, IBIS,Hosp Univ Virgen del Rocio, Seville, Spain, [Saez, Carmen] Univ Seville, CSIC, Inst Biomed Sevilla, IBIS,Hosp Univ Virgen del Rocio, Seville, Spain, [Carnero, Amancio] Univ Seville, CSIC, Inst Biomed Sevilla, IBIS,Hosp Univ Virgen del Rocio, Seville, Spain, [Miguel Marin-Gomez, Luis] Virgen del Rocio Univ Hosp, Dept Gen Surg, Seville, Spain, [Padillo-Ruiz, Javier] Virgen del Rocio Univ Hosp, Dept Gen Surg, Seville, Spain, [Jose Robles-Frias, Maria] Virgen del Rocio Univ Hosp, Dept Pathol, Seville, Spain, [Saez, Carmen] Virgen del Rocio Univ Hosp, Dept Pathol, Seville, Spain, [Jose Robles-Frias, Maria] Virgen del Rocio Univ Hosp, HUVR IBiS Biobank, Seville, Spain, [Garcia-Carbonero, Rocio] Virgen del Rocio Univ Hosp, Dept Med Oncol, Seville, Spain, [Garcia-Carbonero, Rocio] 12 October Univ Hosp, Dept Med Oncol, Madrid, Spain, Spanish Ministry of Economy and Competitivity, ISCIII - FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion, Consejeria de Salud of the Junta de Andalucia, Plan Nacional de I+D+I, and Plan Estatal de I+D+I
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., The authors thank the donors and HUVR-IBiS Biobank (Andalusian Public Health System Biobank and ISCIII-Red de Biobancos PT13/0010/0056) for the human specimens used in this study. We also thank Jorge Martin-Perez for the generous gift of Src gene. The AC lab was supported by grants from the Spanish Ministry of Economy and Competitivity, Plan Nacional de I+D+I 2008-2011, Plan Estatal de I+D+I 2013-2016, ISCIII (Fis: PI12/00137, PI13/02295, PI15/00045, RTICC: RD12/0036/0028) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012 and PI-0096-2014).