Src activity is modulated by oxaliplatin and correlates with outcomes after hepatectomy for metastatic colorectal cancerReportar como inadecuado

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BMC Cancer

, 14:660

Clinical oncology


BackgroundThe nonreceptor tyrosine kinase Src regulates multiple pathways critical to tumor proliferation, chemoresistance, and epithelial-to-mesenchymal transition. It is robustly activated after acute oxaliplatin exposure and in acquired oxaliplatin resistance in vitro and in vivo, but not after 5-fluorouracil 5-FU alone. However, activation of Src and its substrate focal adhesion kinase FAK in metastatic colorectal cancer treated with oxaliplatin has not been investigated. We retrospectively evaluated the activation of Src and FAK in hepatic metastases of colorectal cancer and correlated these findings with the clinical outcomes of patients treated with oxaliplatin.

MethodsSamples from 170 hepatic resections from patients with metastatic colorectal cancer from two cohorts were examined by IHC for expression of Src, activated Src pSrc, FAK, and activated FAK pFAK. Patients in the first cohort 120 patients were analyzed for immunohistochemical protein expression and for survival outcomes. In the second cohort, tissue was collected from 25 patients undergoing sequential hepatic metastasectomies n = 50.

ResultsIn the first cohort, Src activation was positively correlated with pFAK expression P = 0.44, P < 0.001. Patients pretreated with oxaliplatin and 5-FU demonstrated increased expression of pFAK P = 0.017 compared with patients treated with 5-FU alone or irinotecan-5-FU. Total Src expression was associated with the number of neoadjuvant cycles of oxaliplatin P = 0.047. In the second cohort, pFAK expression was higher following exposure to oxaliplatin. When patients were stratified by expression of pFAK and pSrc, an inverse relationship was observed between relapse-free survival rates and levels of both pFAK 21.1 months, 16.5 months, and 7.4 months for low, medium, and high levels of pFAK, respectively; P = 0.026 and pSrc 19.6 months, 13.6 months, and 8.2 months, respectively; P = 0.013. No differences in overall survival were detected.

ConclusionsPatients administered neoadjuvant oxaliplatin demonstrated higher levels of Src pathway signaling in hepatic metastases, a finding associated with poorer relapse-free survival. These results are consistent with prior in vitro studies and support the idea that combining Src inhibition with platinum chemotherapy warrants further investigation in metastatic colorectal cancer.

KeywordsColorectal cancer Metastasis Hepatectomy Src oncogene Focal adhesion kinase Abbreviations5-FU5-fluorouracil

FAKFocal adhesion kinase

pSrcphosphorylated Src

pFAKphosphorylated focal adhesion kinase

FOLFOX5-fluorouracil and oxaliplatin

FOLFIRI5-fluorouracil and irinotecan

CVCoefficient of variation

PBSPhospho-buffered saline.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-14-660 contains supplementary material, which is available to authorized users.

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Autor: Scott Kopetz - Van K Morris - Nila Parikh - Michael J Overman - Zhi-Qin Jiang - Dipen Maru - Paul Elvin - Gary Gallick


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