Src activity is modulated by oxaliplatin and correlates with outcomes after hepatectomy for metastatic colorectal cancer

Background: The 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. Methods: Samples 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). Results: In 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. Conclusions: Patients 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.