dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer: A dual-institutional follow-up with the RTOG 9704 trial

Florencia McAllister, Danielle M. Pineda, Masaya Jimbo, Shruti Lal, Richard A. Burkhart, Jennifer Moughan, Kathryn A. Winter, Kotb Abdelmohsen, Myriam Gorospe, Ana De Jesus Acosta, Rachana H. Lankapalli, Jordan M. Winter, Charles J. Yeo, Agnieska K. Witkiewicz, Christine A. Iacobuzio-Donahue, Daniel Laheru, Jonathan R. Brody

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)688-698
Number of pages11
JournalCancer Biology and Therapy
Volume15
Issue number6
DOIs
StatePublished - 2014

Fingerprint

Deoxycytidine Kinase
Radiation Oncology
Pancreatic Neoplasms
Fluorouracil
Radiotherapy
gemcitabine
Antigens
Adenocarcinoma
Radiation
Survival
Proportional Hazards Models
Pharmaceutical Preparations
Disease-Free Survival
Cultured Cells
Cytoplasm
Therapeutics
Randomized Controlled Trials
Immunohistochemistry

Keywords

  • 5-fluorouracil
  • dCK
  • Gemcitabine
  • HuR
  • Pancreatic cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Molecular Medicine
  • Pharmacology
  • Medicine(all)

Cite this

dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer : A dual-institutional follow-up with the RTOG 9704 trial. / McAllister, Florencia; Pineda, Danielle M.; Jimbo, Masaya; Lal, Shruti; Burkhart, Richard A.; Moughan, Jennifer; Winter, Kathryn A.; Abdelmohsen, Kotb; Gorospe, Myriam; De Jesus Acosta, Ana; Lankapalli, Rachana H.; Winter, Jordan M.; Yeo, Charles J.; Witkiewicz, Agnieska K.; Iacobuzio-Donahue, Christine A.; Laheru, Daniel; Brody, Jonathan R.

In: Cancer Biology and Therapy, Vol. 15, No. 6, 2014, p. 688-698.

Research output: Contribution to journalArticle

McAllister, F, Pineda, DM, Jimbo, M, Lal, S, Burkhart, RA, Moughan, J, Winter, KA, Abdelmohsen, K, Gorospe, M, De Jesus Acosta, A, Lankapalli, RH, Winter, JM, Yeo, CJ, Witkiewicz, AK, Iacobuzio-Donahue, CA, Laheru, D & Brody, JR 2014, 'dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer: A dual-institutional follow-up with the RTOG 9704 trial', Cancer Biology and Therapy, vol. 15, no. 6, pp. 688-698. https://doi.org/10.4161/cbt.28413
McAllister, Florencia ; Pineda, Danielle M. ; Jimbo, Masaya ; Lal, Shruti ; Burkhart, Richard A. ; Moughan, Jennifer ; Winter, Kathryn A. ; Abdelmohsen, Kotb ; Gorospe, Myriam ; De Jesus Acosta, Ana ; Lankapalli, Rachana H. ; Winter, Jordan M. ; Yeo, Charles J. ; Witkiewicz, Agnieska K. ; Iacobuzio-Donahue, Christine A. ; Laheru, Daniel ; Brody, Jonathan R. / dCK expression correlates with 5-fluorouracil efficacy and HuR cytoplasmic expression in pancreatic cancer : A dual-institutional follow-up with the RTOG 9704 trial. In: Cancer Biology and Therapy. 2014 ; Vol. 15, No. 6. pp. 688-698.
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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.

PY - 2014

Y1 - 2014

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.

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