Highlights
- •Trifluridine (FTD) is a cytotoxic component of the metastatic colorectal cancer drug TAS-102.
- •FTD rapid degradation is inhibited by thymidine phosphorylase inhibitor (TPI).
- •Germline polymorphisms of the nucleoside transporter ENT1 regulate the FTD influx/efflux.
- •Transporters multidrug and toxin extrusion 1 (MATE1) and organic cation transporter 2 (OCT2) are involved in TPI excretion.
- •Combined polymorphisms of transporter genes ENT1, MATE1 and OCT2 classify the clinical outcome.
Abstract
Background
Trifluridine (FTD) is an active cytotoxic component of the metastatic colorectal cancer
(mCRC) drug TAS-102, and thymidine phosphorylase inhibitor (TPI) inhibits the rapid
degradation of FTD. We tested whether single nucleotide polymorphisms (SNPs) in genes
involved in FTD metabolism and TPI excretion could predict outcome in patients with
mCRC treated with TAS-102.
Patients and methods
We investigated three different cohorts: a training cohort (n = 52) and a testing
cohort (n = 129) both receiving TAS-102 and a control cohort (n = 52) receiving regorafenib.
SNPs of TK1, ENT1, CNT1, MATE1, MATE2 and OCT2 were analysed by polymerase chain reaction-based direct DNA sequencing.
Results
In the training cohort, patients with any ENT1 rs760370 G allele had a significantly longer progression-free survival (PFS; 3.5
versus 2.1 months, respectively, hazard ratio [HR] 0.44, P = 0.004) and overall survival (OS; 8.7 versus 5.3 months, respectively, HR 0.27,
P = 0.003) than the A/A genotype. These findings were validated in the testing cohort
(P = 0.021 and 0.009 for PFS and OS, respectively). In addition, the combination of
ENT1 rs760370, MATE1 rs2289669 and OCT2 rs316019 SNPs significantly stratified patients with the risk of PFS and OS in both
cohorts (P < 0.001 for PFS and OS in the training cohort; P = 0.053 and 0.025 for PFS and OS, respectively, in the testing cohort). No significant
differences were observed in the control group.
Conclusions
The combination of ENT1, MATE1 and OCT2 SNPs may serve as a predictive and prognostic marker in mCRC patients treated with
TAS-102.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to European Journal of CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Phase I study to determine the safety and pharmacokinetics of oral administration of TAS-102 in patients with solid tumors.Cancer. 2006; 107: 1383-1390
- Therapeutic potential of the dual-targeted TAS-102 formulation in the treatment of gastrointestinal malignancies.Cancer Sci. 2007; 98: 779-789
- Differential activation of cell death and autophagy results in an increased cytotoxic potential for trifluorothymidine compared to 5-fluorouracil in colon cancer cells.Int J Cancer. 2010; 126: 2457-2468
- Discovery and development of clofarabine: a nucleoside analogue for treating cancer.Nat Rev Drug Discov. 2006; 5: 855-863
- Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases.Nat Rev Drug Discov. 2013; 12: 447-464
- The broadly selective human Na+/nucleoside cotransporter (hCNT3) exhibits novel cation-coupled nucleoside transport characteristics.J Biol Chem. 2005; 280: 25436-25449
- Human equilibrative nucleoside transporter 1 (hENT1) in pancreatic adenocarcinoma: towards individualized treatment decisions.Cancers (Basel). 2010; 2: 2044-2054
- Involvement of concentrative nucleoside transporter 1 in intestinal absorption of trifluorothymidine, a novel antitumor nucleoside, in rats.J Pharmacol Exp Ther. 2012; 340: 457-462
- A novel combination antimetabolite, TAS-102, exhibits antitumor activity in FU-resistant human cancer cells through a mechanism involving FTD incorporation in DNA.Int J Oncol. 2004; 25: 571-578
- Trifluorothymidine exhibits potent antitumor activity via the induction of DNA double-strand breaks.Exp Ther Med. 2011; 2: 393-397
- Crucial roles of thymidine kinase 1 and deoxyUTPase in incorporating the antineoplastic nucleosides trifluridine and 2'-deoxy-5-fluorouridine into DNA.Int J Oncol. 2015; 46: 2327-2334
- Trifluorothymidine resistance is associated with decreased thymidine kinase and equilibrative nucleoside transporter expression or increased secretory phospholipase A2.Mol Cancer Ther. 2010; 9: 1047-1057
- Phase I study of TAS-102 treatment in Japanese patients with advanced solid tumours.Br J Cancer. 2012; 107: 429-434
- Investigation of transporters that play an important role in urinary secretion of thymidine phosphorylase inhibitor combined with a novel anti-cancer agent of TAS-102.Drug Metab Rev. 2015; 47: 263
- Transport of asymmetric dimethylarginine (ADMA) by cationic amino acid transporter 2 (CAT2), organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1).Amino Acids. 2013; 45: 989-1002
- A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin.Pharmacogenet Genomics. 2013; 23: 526-534
- Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters.Br J Clin Pharmacol. 2013; 76: 787-796
- Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy.Oncogene. 2003; 22: 7524-7536
- The absence of human equilibrative nucleoside transporter 1 is associated with reduced survival in patients with gemcitabine-treated pancreas adenocarcinoma.Clin Cancer Res. 2004; 10: 6956-6961
- Gemcitabine metabolic and transporter gene polymorphisms are associated with drug toxicity and efficacy in patients with locally advanced pancreatic cancer.Cancer. 2010; 116: 5325-5335
- Investigating the role of nucleoside transporters in the resistance of colorectal cancer to 5-fluorouracil therapy.Cancer Chemother Pharmacol. 2013; 71: 817-823
- A human transporter protein that mediates the final excretion step for toxic organic cations.Proc Natl Acad Sci U S A. 2005; 102: 17923-17928
- Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms.Am J Physiol Ren Physiol. 2010; 298: F997-F1005
- Human mass balance study of TAS-102 using (14)C analyzed by accelerator mass spectrometry.Cancer Chemother Pharmacol. 2016; 77: 515-526
- Cost effectiveness of pharmacogenetic testing for uridine diphosphate glucuronosyltransferase 1A1 before irinotecan administration for metastatic colorectal cancer.Cancer. 2009; 115: 3858-3867
Article info
Publication history
Published online: October 06, 2017
Accepted:
August 30,
2017
Received in revised form:
August 21,
2017
Received:
April 13,
2017
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
