Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src.
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.
Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.
Marco
M
Perez
Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.
Antonio
A
Lucena-Cacace
Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.|Department of General Surgery, Virgen del Rocío University Hospital, Seville, Spain.
Luis Miguel
LM
Marín-Gómez
Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.|Department of General Surgery, Virgen del Rocío University Hospital, Seville, Spain.
Javier
J
Padillo-Ruiz
Department of Pathology, Virgen del Rocío University Hospital, Seville, Spain.|Present address: HUVR-IBiS Biobank, Virgen del Rocío University Hospital, Seville, Spain.
Maria Jose
MJ
Robles-Frias
Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.|Department of Pathology, Virgen del Rocío University Hospital, Seville, Spain.
Carmen
C
Saez
Department of Medical Oncology, Virgen del Rocío University Hospital, Seville, Spain.|Present address: Department of Medical Oncology, 12 of October University Hospital, Madrid, Spain.
Rocio
R
Garcia-Carbonero
Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Seville, Spain.
Amancio
A
Carnero
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000069439:Dasatinib / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000077150:Oxaliplatin; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D019061:src-Family Kinases; D000069439:Dasatinib
Src kinase; biomarkers; cancer treatment; metastatic colorectal carcinoma; pdx models