Effect of ribonucleotide reductase M1 expression on overall survival in patients with pancreatic cancer receiving gemcitabine chemotherapy: A literature‐based meta‐analysis

Abstract

Summary What is known and objective The prognostic value of ribonucleotide reductase M1 (RRM1) in patients with pancreatic cancer receiving gemcitabine chemotherapy has been evaluated in several studies. However, the conclusions remain controversial. Methods By searching the PubMed and Embase databases, we conducted a meta‐analysis to evaluate the prognostic significance of RRM1 expression in patients with pancreatic cancer receiving gemcitabine chemotherapy. Studies were pooled, and the hazard ratio (HR) and its corresponding 95% confidence interval (CI) were calculated. Results Nine relevant articles were included for this meta‐analysis study. Our results revealed that the high‐RRM1 expression patients had significantly poorer overall survival (HR = 1.70, 95% CI = 1.33‐2.16, Pheterogeneity = .061, I2 = 44.8%) and disease‐free survival (HR = 1.84, 95% CI = 1.56‐2.18, Pheterogeneity = .669, I2 = 0%) than the low‐RRM1 expression patients. Furthermore, a statistically significant association between RRM1 expression and OS was found among both Japanese (HR = 1.80, 95% CI = 1.36‐2.37, Pheterogeneity = .843, I2 = 0%) and American patients (HR = 1.76, 95% CI = 1.60‐1.94, Pheterogeneity = .439, I2 = 0%). What is new and conclusion In conclusion, the expression of RRM1 can be considered a predictor of poor survival in patients with pancreatic cancer receiving gemcitabine chemotherapy. RRM1 expression assessment could provide more detailed information for patients with pancreatic cancer and could be used to optimize therapeutic schemes.

Chemoresistance in Pancreatic Cancer

“…Inhibition of RR induced by dFdCDP is the most significant mechanism for the enhancement of gemcitabine activity [20,21]. A recent meta-analysis revealed that patients with high RRM1 expression had largely poorer OS and DFS than those with low RRM1 expression [46,47], suggesting that the expression of RRM1 is an indicator of poor survival in patients with pancreatic cancer accepting gemcitabine chemotherapy [46]. Experiments confirmed that overexpression of RRM1 and RRM2 proteins of the pancreatic cancer cell line can achieve stable genetic gemcitabine resistance [48,49].…”

Cytoplasmic RRM1 activation as an acute response to gemcitabine treatment is involved in drug resistance of pancreatic cancer cells

“…Ribonucleotide reductase large subunit M1 (RRM1) is a rate-limiting enzyme of the DNA synthesis pathway, and is depended on for the conversion of ribonucleotides to dNTPs [ 14 ]. Studies have shown that increased levels of RRM1 are associated with resistance to gemcitabine [ 15 , 16 ]. RRM1 has also been reported to affect disease prognosis of pancreatic cancer.…”

Glycogen synthase kinase‐3β participates in acquired resistance to gemcitabine in pancreatic cancer

“…Putative biochemical mechanisms of gemcitabine resistance include the decreased expression of human equilibrative nucleoside transporter‐1 (hENT1) that is indispensable for cellular uptake of gemcitabine, 36 the inactivation of deoxycytidine kinase (dCK) that is a late‐limiting enzyme for metabolic activation of gemcitabine, 37 and the overexpression of RRM1 that sustains DNA synthesis, thus counteracting the pharmacological action of gemcitabine 29 . These molecular alterations found in the tumors were associated with poor survival of pancreatic cancer patients undergoing treatment with gemcitabine in various clinical settings 38,39 . Recent experimental approaches aimed at overcoming the acquired resistance to gemcitabine include targeting of hENT1 expression by TS inhibitor and bypassing nucleoside transporters by prodrugs.…”

“…29 These molecular alterations found in the tumors were associated with poor survival of pancreatic cancer patients undergoing treatment with gemcitabine in various clinical settings. 38,39 Recent experimental approaches aimed at overcoming the acquired resistance to gemcitabine include targeting of hENT1 expression by TS inhibitor and bypassing nucleoside transporters by prodrugs. Other approaches F I G U R E 4 Changes in expression of RRM1, GSK3β and cell cycle regulatory molecules in BxPC-3 cells and gemcitabine-resistant clones following GSK3β inhibition.…”