title: Src activity is modulated by oxaliplatin and correlates with outcomes after hepatectomy for metastatic colorectal cancer.
abstract: 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.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
authors.forename: Van K
authors.initials: VK
authors.lastname: Morris
authors.forename: Nila
authors.initials: N
authors.lastname: Parikh
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Overman
authors.forename: Zhi-Qin
authors.initials: ZQ
authors.lastname: Jiang
authors.forename: Dipen
authors.initials: D
authors.lastname: Maru
authors.forename: Paul
authors.initials: P
authors.lastname: Elvin
authors.affiliation: Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 0018-4, Houston, TX 77030, USA. ggallick@mdanderson.org.
authors.forename: Gary
authors.initials: G
authors.lastname: Gallick
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D005472:Fluorouracil / Q000627:therapeutic use; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006498:Hepatectomy; D006801:Humans; D000077146:Irinotecan; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000627:therapeutic use*; D000077150:Oxaliplatin; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D016392:Proto-Oncogene Proteins pp60(c-src); D005472:Fluorouracil; D002166:Camptothecin