The relationship between RRM1 gene polymorphisms and effectiveness of gemcitabine-based first-line chemotherapy in advanced NSCLC patient

Abstract

PurposeChemotherapy with platinum compounds and gemcitabine is frequently used in first-line treatment of advanced non-small cell lung cancer (NSCLC) patients in which tyrosine kinase inhibitors (EGFR or ALK) cannot be administered. Unfortunately, less than half of the patients achieve the benefit from chemotherapy. Gemcitabine is an analog of deoxycytidine (pyrimidine antimetabolite) with antitumor activity. The excess of deoxycytidine synthesized by RRM1 enzyme activity may be a cause of competitive displacement of gemcitabine, which reduces the efficacy of this cytostatic. The aim of this study was to determine the association between single nucleotide polymorphisms (SNPs) of the RRM1 promoter (−37C>A, −524C>T) and the effectiveness of first-line chemotherapy based on platinum compounds and gemcitabine in NSCLC patients.Patients and methodsSNPs were determined by SNaPshot PCR® in DNA isolated from peripheral blood of 91 NSCLC patients.ResultsThe median progression-free survival (PFS) was significantly longer in carriers of AA (−37C>A) as well as CC (−524C>T) genotype of RRM1 compared to patients with other genotypes (10.5 vs 3.5 months, p = 0.0437; HR = 2.17, 95 % CI 1.02–4.62 and 10.5 vs 3.5 months, p = 0.0343; HR = 2.12, 95 % CI 1.06–4.27). In addition, the CC genotype carriers (−37C>A) showed a significant increase in the risk of shortening overall survival (OS) in comparison to patients with AA or AC genotypes (9.5 vs 18 months, p = 0.0193; HR = 2.13, 95 % CI 1.13–4.03).ConclusionsPresence of rare AA (−37C>A) and CC (−524C>T) genotypes of the RRM1 may be favorable predictive factors for chemotherapy with platinum compounds and gemcitabine in NSCLC patients.

<p>Genetic Polymorphisms and the Efficacy of Platinum-Based Chemotherapy: Review</p>

“… Polymorphism of RRM1 genes could be a predictor factor of PBC-Gemcitabine combination. [ 125 ] RRM1 rs11030813 CC have a significance association with better PFS PFS 10.5 vs 3.5 months, p = 0.0343; HR = (2.12, 95% CI 1.06–4.27). 26 403 Patients, NSCLC Asian OCT2 rs316019 Association with hepatotoxicity (P = 0.026) and hematology toxicity (P=0.039) OCT2 rs316019, MATE1 rs2289669, and ABCC2 rs717620 could be a clinical marker, toxicity, and PBC response.…”

Thrombin is a therapeutic target for non-small-cell lung cancer to inhibit vasculogenic mimicry formation

“…Five weeks after injection of tumor cells, mice injected with control cells had large tumors with an average weight of 1.4 ± 0.4 g and a volume of 884.9 ± 181.4 mm 3 . Interestingly, tumors from the PAR-1-deficient group were smaller than those from the NC group, with an average weight of 0.41 ± 0.10 g and a volume of 178.4 ± 86.7 mm 3 (Fig. 5e, f).…”

“… 2 Even if NSCLC patients are treated with chemotherapy or radiotherapy, the incidence of recurrence is still high. 3 , 4 Compared with traditional chemotherapy, precise tumor treatment is helpful to improve the treatment effect and quality of life. Targeted therapy has become an important means of disease treatment for NSCLC patients.…”

mTORC2 regulates ribonucleotide reductase to promote DNA replication and gemcitabine resistance in non-small cell lung cancer

“…Increased capacity for DNA repair and replication fork restart was considered as the main causes of gemcitabine resistance [7] . Although a group of effectors have been identified as predictive markers of gemcitabine resistance including RRM1, XRCC1, POLA2, most of these studies lacked molecular mechanisms and therapeutic relevance [8] , [9] , [10] .…”