RRM1 Modulated In Vitro and In Vivo Efficacy of Gemcitabine and Platinum in Non–Small-Cell Lung Cancer

Abstract

The results strongly suggest that tumoral RRM1 expression is a major predictor of disease response to gemcitabine/platinum chemotherapy. ERCC1 expression is predictive of response albeit to a lesser degree.

Silencing of ribonucleotide reductase subunit M1 potentiates the antitumor activity of gemcitabine in resistant cancer cells

“…9,[12][13][14][15][16][17][18] Taken together, these findings demonstrate that RRM1 overexpression plays a key role in gemcitabine resistance. Therefore, the downregulation of RRM1 expression may increase the susceptibility of resistant cancer cells to gemcitabine.…”

“…The involvement of RRM1 overexpression in gemcitabine resistance had been documented in various cancers, including non-small cell lung cancer, pancreatic cancer, breast cancer and biliary tract cancer. 9,[12][13][14][15][16][17][18] Thus, it was proposed that knocking down of RRM1 expression can potentiate the siRNA complexes ( Fig. 2C and D), demonstrating that the PEI-RRM1 siRNA complexes downregulated the expression of the RRM1 protein in TC-1-GR tumor tissues in mice.…”

“…4,5 RRM1 has been identified as the key molecule in determining the efficacy of gemcitabine. The overexpression of RRM1 had been repeatedly reported in gemcitabine-resistant cancer cells both in vitro and in vivo, [6][7][8][9][10][11] and RRM1 overexpression through the transfection of a lung cancer cell line led to gemcitabine resistance as well. 9 …”

ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair

“…This highlights the multifactorial nature of platinum resistance and therefore the difficulty in using DNA repair proteins as markers of platinum resistance in the clinic. Some trials have found an association between ERCC1 and response to cisplatin combination therapy [28][29][30], but many more have found no association [31][32][33][34][35]. High ERCC1 may correlate with platinum resistance, but low or absent ERCC1 may not always indicate sensitivity as the H69CIS200 and H69OX400 when actively dividing show no change in ERCC1 despite being platinum resistant.…”

Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer

“…20,21 In particular, an increase in the expression of the RRM1 has been associated with gemcitabine resistance in NSCLC cell lines, 22 while clinical studies demonstrated that NSCLC patients with low mRNA expression benefited from gemcitabine-cisplatin chemotherapy. 23,24 In contrast, high expression of RRM1 protein was significantly associated with longer survival in NSCLC who received only surgical treatment, suggesting the use of RRM1 to select patients to be treated with gemcitabine-based adjuvant chemotherapy. 25 However, further work is required to better elucidate RRM1 transcriptional control.…”