ABCC11 gene polymorphism as a potential predictive biomarker for an oral 5-fluorouracil derivative drug S-1 treatment in non-small cell lung cancer
- 117 Downloads
ABCC11/MRP8 (ABCC11) is an ATP-binding cassette transporter that is involved in regulating cellular sensitivity and resistance for many anti-cancer drugs. Since 5-fluorouracil (5-FU) is one of the substrates for ABCC11, we examined whether ABCC11 is a predictive marker for an oral 5-FU derivative drug S-1 treatment in non-small cell lung cancer (NSCLC).
Real-time PCR and MTS assay were carried on 21 human NSCLC cell lines. The drug resistance capabilities of ABCC11 are evaluated by analyzing the resistance profiles of a clone of HeLa cell in which the pump was ectopically expressed. Blood samples of 106 NSCLC patients were collected.
There was a significant correlation between dihydropyrimidine dehydrogenase (DPD) gene expression and the IC50 for 5-FU. We then classified NSCLC cell lines into two groups based on the phenotype of the SNP538 (G > A) in ABCC11: a combined G/G and G/A group, and an A/A group. The distribution of the IC50 for 5-FU in combination with a potent inhibitor of DPD 5-chloro-2, 4-dihydropyrimidine (CDHP), which is contained in S-1, showed a significant reduction in the A/A group compared with the combined G/G and G/A group. Next, the clinical usefulness of the ABCC11 SNP in treatment containing S-1 was examined in 106 NSCLC patients, and the disease control rate was found to be significantly better in the A/A group than in the combined G/G and G/A group.
These results indicate that the SNP538(G > A) in the ABCC11 gene is a potential determinant for S-1 treatment.
KeywordsABCC11/MRP8 5-fluorouracil (5-FU) S-1 Single-nucleotide polymorphism (SNP) Thymidylate synthase (TS)
This study was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (MEXT/JSPSKAKENHI23591156).
Compliance with ethical standards
Conflict of interest
All the authors declare that they have no conflict of interest.
Informed consent was obtained from all individual participants included in the study.
- 2.Ishikawa Y, Kubota T, Otani Y, Watanabe M, Teramoto T, Kumai K, Kitajima M, Takechi T, Okabe H, Fukushima M (1999) Dihydropyrimidine dehydrogenase activity and messenger RNA level may be related to the antitumor effect of 5-fluorouracil on human tumor xenografts in nude mice. Clin Cancer Res 5:883–889PubMedGoogle Scholar
- 4.Oguri T, Achiwa H, Bessho Y, Muramatsu H, Maeda H, Niimi T, Sato S, Ueda R (2005) The role of thymidylate synthase and dihydropyrimidine dehydrogenase in resistance to 5-fluorouracil in human lung cancer cells. Lung Cancer 49:345–351. https://doi.org/10.1016/j.lungcan.2005.05.003 CrossRefPubMedGoogle Scholar
- 6.Kato H, Ichinose Y, Ohta M, Hata E, Tsubota N, Tada H, Watanabe Y, Wada H, Tsuboi M, Hamajima N, Ohta M (2004) A randomized trial of adjuvant chemotherapy with uracil-tegafur for adenocarcinoma of the lung. N Engl J Med 350:1713–1721. https://doi.org/10.1056/NEJMoa032792 CrossRefPubMedGoogle Scholar
- 9.Chen ZS, Robey RW, Belinsky MG, Shchaveleva I, Ren XQ, Sugimoto Y, Ross DD, Bates SE, Kruh GD (2003) Transport of methotrexate, methotrexate polyglutamates, and 17beta-estradiol 17-(beta-D-glucuronide) by ABCG2: effects of acquired mutations at R482 on methotrexate transport. Cancer Res 63:4048–4054PubMedGoogle Scholar
- 10.Guo Y, Kotova E, Chen ZS, Lee K, Hopper-Borge E, Belinsky MG, Kruh GD (2003) MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2′,3′-dideoxycytidine and 9′-(2′-phosphonylmethoxyethyl)adenine. J Biol Chem 278:29509–29514. https://doi.org/10.1074/jbc.M304059200 CrossRefPubMedGoogle Scholar
- 16.Fujiwara H, Terashima M, Irinoda T, Takagane A, Abe K, Kashiwaba M, Oyama K, Takahashi M, Maesawa C, Saito K, Takechi T, Fukushima M (2002) Quantitative measurement of thymidylate synthase and dihydropyrimidine dehydrogenase mRNA level in gastric cancer by real-time RT-PCR. Jpn J Cancer Res 93:1342–1350CrossRefGoogle Scholar
- 17.Ma T, Zhu ZG, Ji YB, Zhang Y, Yu YY, Liu BY, Yin HR, Lin YZ (2004) Correlation of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase with sensitivity of gastrointestinal cancer cells to 5-fluorouracil and 5-fluoro-2′-deoxyuridine. World J Gastroenterol 10:172–176PubMedPubMedCentralGoogle Scholar
- 18.Salonga D, Danenberg KD, Johnson M, Metzger R, Groshen S, Tsao-Wei DD, Lenz HJ, Leichman CG, Leichman L, Diasio RB, Danenberg PV (2000) Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 6:1322–1327PubMedGoogle Scholar
- 20.Okamoto I, Yoshioka H, Morita S, Ando M, Takeda K, Seto T, Yamamoto N, Saka H, Asami K, Hirashima T, Kudoh S, Satouchi M et al (2010) Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer: results of a west Japan oncology group study. J Clin Oncol 28:5240–5246. https://doi.org/10.1200/JCO.2010.31.0326 CrossRefPubMedGoogle Scholar
- 21.Yoshioka H, Okamoto I, Morita S, Ando M, Takeda K, Seto T, Yamamoto N, Saka H, Atagi S, Hirashima T, Kudoh S, Satouchi M et al (2013) Efficacy and safety analysis according to histology for S-1 in combination with carboplatin as first-line chemotherapy in patients with advanced non-small-cell lung cancer: updated results of the West Japan Oncology Group LETS study. Ann Oncol 24:1326–1331. https://doi.org/10.1093/annonc/mds629 CrossRefPubMedGoogle Scholar
- 22.Nokihara H, Lu S, Mok TSK, Nakagawa K, Yamamoto N, Shi YK, Zhang L, Soo RA, Yang JC, Sugawara S, Nishio M, Takahashi T et al (2017) Randomized controlled trial of S-1 versus docetaxel in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy (East Asia S-1 Trial in Lung Cancer). Ann Oncol 28:2698–2706. https://doi.org/10.1093/annonc/mdx419 CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M et al (2015) Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 373:1627–1639. https://doi.org/10.1056/NEJMoa1507643 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N et al (2015) Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 373:123–135. https://doi.org/10.1056/NEJMoa1504627 CrossRefPubMedPubMedCentralGoogle Scholar
- 25.Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, Park K, Smith D, Artal-Cortes A, Lewanski C, Braiteh F, Waterkamp D et al (2016) Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387:1837–1846. https://doi.org/10.1016/S0140-6736(16)00587-0 CrossRefPubMedGoogle Scholar
- 26.Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ et al (2016) Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387:1540–1550. https://doi.org/10.1016/S0140-6736(15)01281-7 CrossRefPubMedGoogle Scholar
- 27.Ichinose Y, Yoshimori K, Sakai H, Nakai Y, Sugiura T, Kawahara M, Niitani H (2004) S-1 plus cisplatin combination chemotherapy in patients with advanced non-small cell lung cancer: a multi-institutional phase II trial. Clin Cancer Res 10:7860–7864. https://doi.org/10.1158/1078-0432.ccr-04-1200 CrossRefPubMedGoogle Scholar
- 29.Shaul YD, Freinkman E, Comb WC, Cantor JR, Tam WL, Thiru P, Kim D, Kanarek N, Pacold ME, Chen WW, Bierie B, Possemato R et al (2014) Dihydropyrimidine accumulation is required for the epithelial-mesenchymal transition. Cell 158:1094–1109. https://doi.org/10.1016/j.cell.2014.07.032 CrossRefPubMedPubMedCentralGoogle Scholar
- 32.Toyoda Y, Sakurai A, Mitani Y, Nakashima M, Yoshiura K, Nakagawa H, Sakai Y, Ota I, Lezhava A, Hayashizaki Y, Niikawa N, Ishikawa T (2009) Earwax, osmidrosis, and breast cancer: why does one SNP (538G > A) in the human ABC transporter ABCC11 gene determine earwax type? FASEB J 23:2001–2013. https://doi.org/10.1096/fj.09-129098 CrossRefPubMedGoogle Scholar
- 35.Tsuchiya T, Arai J, Matsumoto K, Miyazaki T, Honda S, Tagawa T, Nakamura A, Taniguchi H, Sano I, Akamine S, Muraoka M, Hisano H et al (2016) Prognostic Impact of the ABCC11/MRP8 Polymorphism in Adjuvant Oral Chemotherapy with S-1 for Non-Small Cell Lung Cancer. Chemotherapy 61:77–86. https://doi.org/10.1159/000438942 CrossRefPubMedGoogle Scholar
- 36.Hotta K, Fujiwara Y, Kiura K, Takigawa N, Tabata M, Ueoka H, Tanimoto M (2007) Relationship between response and survival in more than 50,000 patients with advanced non-small cell lung cancer treated with systemic chemotherapy in 143 phase III trials. J Thorac Oncol 2:402–407. https://doi.org/10.1097/01.JTO.0000268673.95119.c7 CrossRefPubMedGoogle Scholar