TY - JOUR
T1 - dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer
T2 - A dual-institutional follow-up with the RTOG 9704 trial
AU - McAllister, Florencia
AU - Pineda, Danielle M.
AU - Jimbo, Masaya
AU - Lal, Shruti
AU - Burkhart, Richard A.
AU - Moughan, Jennifer
AU - Winter, Kathryn A.
AU - Abdelmohsen, Kotb
AU - Gorospe, Myriam
AU - De Jesus Acosta, Ana
AU - Lankapalli, Rachana H.
AU - Winter, Jordan M.
AU - Yeo, Charles J.
AU - Witkiewicz, Agnieska K.
AU - Iacobuzio-Donahue, Christine A.
AU - Laheru, Daniel
AU - Brody, Jonathan R.
N1 - Funding Information:
F.M. was supported by NIGMS T32GMO66691, 2012 Pancreatic Cancer Action Network-AACR Fellowship, in memory of Samuel Stroum, Grant Number 12-40-25-MCAL and Conquer Cancer Foundation Young Investigator Award 2012. J.R.B. was in part supported by resources provided by AACR-Pancreatic Cancer Action Network and A Research Scholar Grant from the American Cancer Society. M.G. and K.A. were supported by the NIA-IRP, NIH. This project was supported by the RTOG Translational Research Program (seed grant #78), RTOG grant U10 CA21661, CCOP grant U10 CA37422 from the National Cancer Institute (NCI), and the Pennsylvania Department of Health Formula Grant 4100057652. No part of this manuscript has been submitted to any other journal.
PY - 2014/6
Y1 - 2014/6
N2 - 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.
AB - 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.
KW - 5-fluorouracil
KW - Gemcitabine
KW - HuR
KW - Pancreatic cancer
KW - dCK
UR - http://www.scopus.com/inward/record.url?scp=84901704779&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901704779&partnerID=8YFLogxK
U2 - 10.4161/cbt.28413
DO - 10.4161/cbt.28413
M3 - Article
C2 - 24618665
AN - SCOPUS:84901704779
SN - 1538-4047
VL - 15
SP - 688
EP - 698
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 6
ER -