RT Journal Article
T1 Dasatinib, a Src inhibitor, sensitizes liver metastatic colorectal carcinoma to oxaliplatin in tumors with high levels of phospho-Src
A1 Perez, Marco
A1 Lucena-Cacace, Antonio
A1 Miguel Marin-Gomez, Luis
A1 Padillo-Ruiz, Javier
A1 Jose Robles-Frias, Maria
A1 Saez, Carmen
A1 Garcia-Carbonero, Rocio
A1 Carnero, Amancio
K1 metastatic colorectal carcinoma
K1 cancer treatment
K1 biomarkers
K1 Src kinase
K1 pdx models
K1 Human-colon-carcinoma
K1 Cancer cell-lines
K1 Tyrosine kinase
K1 Family kinases
K1 Therapeutic implications
K1 Down-regulation
K1 Breast-cancer
K1 Solid tumors
K1 C-src
K1 Resistance
AB 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.
PB Impact journals llc
YR 2016
FD 2016-05-31
LK http://hdl.handle.net/10668/19427
UL http://hdl.handle.net/10668/19427
LA en
DS RISalud
RD Apr 10, 2025