Introduction: ABCC11/MRP8 (ABCC11) is an ATP-binding cassette transporter that is involved in regulating cellular sensitivity and resistance for many anti-cancer drugs including antifolates 5-fluorouracil (5-FU), pemetrexed and methotrexate. ABCC11 has functional genetic variant which regulate the protein expression of ABCC11. However, the relationship between the genetic variant of ABCC11 and the efficacy of anticancer drugs remains to be elucidated. An oral 5-FU derivative S-1 composed of tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP; a potent inhibitor of dehydropyrimidine dehydrogenase), and potassium oxonate, is used against non-small cell lung cancer (NSCLC) treatment; however the biomarker for S-1 is not fully examined. In this study, we examined whether ABCC11 single nucleotide polymorphism (SNP) which regulate the expression of ABCC11 is related with the efficacy of S-1.
Method and results: We introduced ABCC11 showing 538G or 538A expression vector and parental plasmid into HeLa cells and established HeLa/ABCC-538G, HeLa/ABCC-538A and HeLa/mock cells, respectively. The protein expression of ABCC11 was higher in the HeLa/ABCC-538-G cell than in the other cells. Futhermore, the IC50 for 5-FU with CDHP was 0.94, 9.75 and 0.64 times higher in the HeLa, HeLa/ABCC-538G and HeLa/ABCC-538A cells than in the HeLa/mock cells, respectively. This result indicates that this ABCC11 SNP is related with 5-FU cytotxocity. Then we analyzed 21 human NSCLC cell lines, classifing NSCLC cell lines into two groups based on the genotype of the SNP 538G>A in ABCC11: a combined G/G and G/A genotype group, and an A/A genotype group. The distribution of the cytotoxicity for 5-FU in combination with CDHP was significantly lower in the A/A genotype group than in the combined G/G and G/A genotype group. Next, we examined the clinical usefulness of the ABCC11 SNP in S-1 treatment of 68 NSCLC patients. In these 68 patients, the median progression-free survival (PFS) was 73days, and the disease control rate was 50%. These data was similar to previous reports. Classified these 68 patients into each ABCC11 538G>A genotype group, we found that the disease control rate was significantly better in the A/A genotype group than in the combined G/G and G/A genotype group (A/A:59.2%, G/G and G/A:35.7%, respectively), but the PFS had no significant difference between these two genotype groups.
Conclusion: SNP 538G>A in the ABCC11 gene is a potential determinant for S-1 treatment in NSCLC.
Citation Format: Satoshi Fukuda, Takehiro Uemura, Tetsuya Oguri, Akira Takeuchi, Kazuki Sone, Takamitsu Asano, Yoshihiro Kanemitsu, Masaya Takemura, Hirotsugu Ohkubo, Ken Maeno, Yutaka Ito, Akio Niimi. ABCC11 gene polymorphism as a potential predictive biomarker for an oral 5-fluorouracil derivative drug S-1 treatment in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3895.