title: dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer: a dual-institutional follow-up with the RTOG 9704 trial.
abstract: Deoxycytidine kinase (dCK) and human antigen R (HuR) have been associated with response to gemcitabine in small studies. The present study investigates the prognostic and predictive value of dCK and HuR expression levels for sensitivity to gemcitabine and 5-fluorouracil (5-FU) in a large phase III adjuvant trial with chemoradiation backbone in pancreatic ductal adenocarcinoma (PDA). The dCK and HuR expression levels were determined by immunohistochemistry on a tissue microarray of 165 resected PDAs from the Radiation Therapy Oncology Group (RTOG) 9704 trial. Association with overall survival (OS) and disease-free survival (DFS) status were analyzed using the log-rank test and the Cox proportional hazards model. Experiments with cultured PDA cells were performed to explore mechanisms linking dCK and HuR expression to drug sensitivity. dCK expression levels were associated with improved OS for all patients analyzed from RTOG 9704 (HR: 0.66, 95% CI [0.47-0.93], P = 0.015). In a subset analysis based on treatment arm, the effect was restricted to patients receiving 5-FU (HR: 0.53, 95% CI [0.33-0.85], P = 0.0078). Studies in cultured cells confirmed that dCK expression rendered cells more sensitive to 5-FU. HuR cytoplasmic expression was neither prognostic nor predictive of treatment response. Previous studies along with drug sensitivity and biochemical studies demonstrate that radiation interferes with HuR's regulatory effects on dCK, and could account for the negative findings herein based on the clinical study design (i.e., inclusion of radiation). Finally, we demonstrate that 5-FU can increase HuR function by enhancing HuR translocation from the nucleus to the cytoplasm, similar to the effect of gemcitabine in PDA cells. For the first time, in the pre-treatment tumor samples, dCK and HuR cytoplasmic expression were strongly correlated (chi-square P = 0.015). This dual-institutional follow up study, in a multi-institutional PDA randomized clinical trial, observed that dCK expression levels were prognostic and had predictive value for sensitivity to 5-FU.
authors.affiliation: Departments of Medical Oncology and Pathology; Johns Hopkins University; Baltimore, MD USA; Department of Medicine; Division of Clinical Pharmacology; Johns Hopkins University; Baltimore, MD USA.
authors.forename: Florencia
authors.initials: F
authors.lastname: McAllister
authors.affiliation: Department of Surgery; Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Pineda
authors.affiliation: Department of Surgery; Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA.
authors.forename: Masaya
authors.initials: M
authors.lastname: Jimbo
authors.affiliation: Department of Surgery; Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Lal
authors.affiliation: Department of Surgery; Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Burkhart
authors.affiliation: RTOG Statistical Center; Philadelphia, PA USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Moughan
authors.affiliation: RTOG Statistical Center; Philadelphia, PA USA.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Winter
authors.affiliation: Laboratory of Genetics; National Institute on Aging Intramural Research Program; National Institutes of Health; Baltimore, MD USA.
authors.forename: Kotb
authors.initials: K
authors.lastname: Abdelmohsen
authors.affiliation: Laboratory of Genetics; National Institute on Aging Intramural Research Program; National Institutes of Health; Baltimore, MD USA.
authors.forename: Myriam
authors.initials: M
authors.lastname: Gorospe
authors.affiliation: Departments of Medical Oncology and Pathology; Johns Hopkins University; Baltimore, MD USA.
authors.forename: Ana de Jesus
authors.initials: Ade J
authors.lastname: Acosta
authors.affiliation: Departments of Medical Oncology and Pathology; Johns Hopkins University; Baltimore, MD USA.
authors.forename: Rachana H
authors.initials: RH
authors.lastname: Lankapalli
authors.affiliation: Department of Surgery; Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Winter
authors.affiliation: Department of Surgery; Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA.
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Yeo
authors.affiliation: Department of Pathology; The University of Texas Southwestern Medical Center; Dallas, TX USA.
authors.forename: Agnieska K
authors.initials: AK
authors.lastname: Witkiewicz
authors.affiliation: Departments of Medical Oncology and Pathology; Johns Hopkins University; Baltimore, MD USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: Departments of Medical Oncology and Pathology; Johns Hopkins University; Baltimore, MD USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.affiliation: Department of Surgery; Division of Surgical Research; The Jefferson Pancreas, Biliary, and Related Cancer Center; Jefferson Medical College; Thomas Jefferson University; Philadelphia, PA USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Brody
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology* / Q000627:therapeutic use; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D059248:Chemoradiotherapy; D003593:Cytoplasm / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000235:genetics / Q000378:metabolism*; D018572:Disease-Free Survival; D051959:ELAV Proteins / Q000378:metabolism*; D000067780:ELAV-Like Protein 1; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D015999:Multivariate Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D021381:Protein Transport; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D051959:ELAV Proteins; D000067780:ELAV-Like Protein 1; C098770:ELAVL1 protein, human; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D005472:Fluorouracil; D000093542:Gemcitabine
keywords: 5-fluorouracil; HuR; dCK; gemcitabine; pancreatic cancer