Abstract 3615: A SNP538(G>A) in ABCC11/MRP8 determines sensitivity for antimetabolites

Abstract

Abstract Anti-metabolic drugs, such as 5-fluorouracil (5-FU) derivatives and antifolate drugs, such as methotrexate (MTX) and pemetrexed (MTA) are often used for widespread cancer treatment in current clinical practice. 5-FU is often used with 5-chloro-2, 4-dehydropyrimidine (CDHP) which inhibits degradation of 5-FU by inactivating dehydropyrimidine dehydrogenase (DPD) as DPD inhibitory fluoropyrimidines (DIF) in clinical because it is known that there is inverse correlation between DPD and sensitivity for 5-FU. MTA is new generation antifolate and the treatment with MTA in combination with cisplatin provides a similar efficacy, with better tolerability and more convenient administration than existing platinum doublet treatments for advanced-stage non-small-cell lung cancer (NSCLC). Because thymidylate synthase (TS) gene which expression is higher in squamous cell carcinoma compared with adenocarcinoma is considered as the most powerful molecule for resistant to MTA, MTA is only used for non-squamous cell lung cancer treatment. Thus, like DPD and TS gene, biomarkers for these anti-metabolic anti-cancer drugs are partially known. However, we can't predict the effects of these anti-metabolic drugs for cancer treatment from these biomarkers because DPD is inactivated by its inhibitor in advance and the MTA isn't used for therapy of squamous cell carcinoma in which TS expression is high. So we need to find new biomarker for anti-metabolic anti-cancer drugs which is available for clinical use. ABCC11/MRP8 (ABCC11) is one of the ATP-binding cassette (ABC) transporters which involve the resistance for some anti-cancer drugs. ABCC11 gene has a nonsynonymous SNP 538(G>A) which is important for determination of the type of human earwax that is expressed. We have previously shown that ABCC11 directly confers resistance to MTA and 5-FU by enhancing efflux of the intracellular anti-cancer drug. Therefore we examined whether ABCC11 is a predictive marker for MTA and 5-FU sensitivity in NSCLC. At first, we analyzed the relationship between the ABCC11 gene expression and IC50 for MTA or 5-FU in NSCLC cells, but there was no correlation. Next, we classified NSCLC cell lines into two groups based on the phenotype of SNP538(G>A) in ABCC11: combined G/G and G/A group and A/A group. Then we compared the distribution of the IC50 for MTA and found that the A/A group showed a significant reduction of the IC50 compared with combined G/G and G/A group in adenocarcinoma cell lines. We also compared the distribution of the IC50 for 5-FU in combination with CDHP in NSCLC cell lines and found same result. These results indicate that the SNP(538G>A) in ABCC11 gene is an important determinant for sensitivity of MTA and 5-FU under inhibition of DPD. Our results may suggest that ABCC11 SNPs is one of the biomarkers for MTA and DIF. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3615. doi:1538-7445.AM2012-3615