Current standard treatments for metastatic colorectal cancer (CRC) are based on combination regimens with one of the two chemotherapeutic drugs, irinotecan or oxaliplatin. However, drug resistance frequently limits the clinical efficacy of these therapies. In order to gain new insights into mechanisms associated with chemoresistance, and departing from three distinct CRC cell models, we generated a panel of human colorectal cancer cell lines with acquired resistance to either oxaliplatin or irinotecan. We characterized the resistant cell line variants with regards to their drug resistance profile and transcriptome, and matched our results with datasets generated from relevant clinical material to derive putative resistance biomarkers. We found that the chemoresistant cell line variants had distinctive irinotecan- or oxaliplatin-specific resistance profiles, with non-reciprocal cross-resistance. Furthermore, we could identify several new, as well as some previously described, drug resistance-associated genes for each resistant cell line variant. Each chemoresistant cell line variant acquired a unique set of changes that may represent distinct functional subtypes of chemotherapy resistance. In addition, and given the potential implications for selection of subsequent treatment, we also performed an exploratory analysis, in relevant patient cohorts, of the predictive value of each of the specific genes identified in our cellular models.

Aarhus University Hospital Department of Molecular Medicine Aarhus Denmark

Masaryk University Faculty of Medicine Institute of Biostatistics and Analyses Brno Czech Republic

SIB Swiss Institute of Bioinformatics Bioinformatics Core Facility Lausanne Switzerland; University of Lausanne Ludwig Center for Cancer Research Lausanne Switzerland; University of Lausanne Oncology Department Lausanne Switzerland

Technical University of Denmark Department for Systems Biology Center for Biological Sequence Analysis Lyngby Denmark

University Hospital Gasthuisberg Digestive Oncology Unit Leuven Belgium

University Hospital of Geneva Oncosurgery Unit Geneva Switzerland

University of Copenhagen Faculty of Health and Medical Sciences Department of Veterinary Disease Biology Frederiksberg Denmark

University of Lausanne University Institute of Pathology Lausanne Switzerland

University of Southern Denmark Institute of Clinical Research Oncology Unit Odense Denmark

University of Southern Denmark Institute of Clinical Research Pathology Unit Odense Denmark

See more in PubMed

Alexopoulou, D.K. , Papadopoulos, I.N. , Scorilas, A. , 2013. Clinical significance of kallikrein-related peptidase (KLK10) mRNA expression in colorectal cancer. Clin. Biochem. 46, 1453–1461. PubMed

Allen, J.D. , van Loevezijn, A. , Lakhai, J.M. , van der Valk, M. , van Tellingen, O. , Reid, G. , Schellens, J.H. , Koomen, G.J. , Schinkel, A.H. , 2002. Potent and specific inhibition of the breast cancer resistance protein multidrug transporter in vitro and in mouse intestine by a novel analogue of fumitremorgin C. Mol. Cancer Ther. 1, 417–425. PubMed

Ashburner, M. , Ball, C.A. , Blake, J.A. , Botstein, D. , Butler, H. , Cherry, J.M. , Davis, A.P. , Dolinski, K. , Dwight, S.S. , Eppig, J.T. , Harris, M.A. , Hill, D.P. , Issel-Tarver, L. , Kasarskis, A. , Lewis, S. , Matese, J.C. , Richardson, J.E. , Ringwald, M. , Rubin, G.M. , Sherlock, G. , Gene Ontology Consortium2000. Gene ontology: tool for the unification of biology. Nat. Genet. 25, 25–29. PubMed PMC

Benjamini, Y. , Hochberg, Y. , 1995. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Statist. Soc. B 57, 289–300.

Beretta, G.L. , Perego, P. , Zunino, F. , 2006. Mechanisms of cellular resistance to camptothecins. Curr. Med. Chem. 13, 3291–3305. PubMed

Birkenkamp-Demtroder, K. , Hahn, S.A. , Mansilla, F. , Thorsen, K. , Maghnouj, A. , Christensen, R. , Oster, B. , Orntoft, T.F. , 2013. Keratin23 (KRT23) knockdown decreases proliferation and affects the DNA damage response of colon cancer cells. PloS One 8, e73593 PubMed PMC

Bolstad, B.M. , Irizarry, R.A. , Astrand, M. , Speed, T.P. , 2003. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185–193. PubMed

Boyer, J. , McLean, E.G. , Aroori, S. , Wilson, P. , McCulla, A. , Carey, P.D. , Longley, D.B. , Johnston, P.G. , 2004. Characterization of p53 wild-type and null isogenic colorectal cancer cell lines resistant to 5-fluorouracil, oxaliplatin, and irinotecan. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 10, 2158–2167. PubMed

Braun, M.S. , Richman, S.D. , Quirke, P. , Daly, C. , Adlard, J.W. , Elliott, F. , Barrett, J.H. , Selby, P. , Meade, A.M. , Stephens, R.J. , Parmar, M.K. , Seymour, M.T. , 2008. Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. J. Clin. Oncol. 26, 2690–2698. PubMed

Brozic, P. , Turk, S. , Rizner, T.L. , Gobec, S. , 2011. Inhibitors of aldo-keto reductases AKR1C1-AKR1C4. Curr. Med. Chem. 18, 2554–2565. PubMed

Budinska, E. , Popovici, V. , Tejpar, S. , D'Ario, G. , Lapique, N. , Sikora, K.O. , Di Narzo, A.F. , Yan, P. , Hodgson, J.G. , Weinrich, S. , Bosman, F. , Roth, A. , Delorenzi, M. , 2013. Gene expression patterns unveil a new level of molecular heterogeneity in colorectal cancer. J. Pathol. 231, 63–76. PubMed PMC

Burgess, D.J. , Doles, J. , Zender, L. , Xue, W. , Ma, B. , McCombie, W.R. , Hannon, G.J. , Lowe, S.W. , Hemann, M.T. , 2008. Topoisomerase levels determine chemotherapy response in vitro and in vivo. Proc. Natl. Acad. Sci. U. S. A. 105, 9053–9058. PubMed PMC

Cancer Genome Atlas, N, 2012. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337. PubMed PMC

Candeil, L. , Gourdier, I. , Peyron, D. , Vezzio, N. , Copois, V. , Bibeau, F. , Orsetti, B. , Scheffer, G.L. , Ychou, M. , Khan, Q.A. , Pommier, Y. , Pau, B. , Martineau, P. , Del Rio, M. , 2004. ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan-treated metastases. International journal of cancer. J. Int. Du Cancer 109, 848–854. PubMed

Cunningham, D. , Atkin, W. , Lenz, H.J. , Lynch, H.T. , Minsky, B. , Nordlinger, B. , Starling, N. , 2010. Colorectal cancer. Lancet 375, 1030–1047. PubMed

Fais, S. , De, M.A. , Lozupone, F. , 2005. The role of FAS to ezrin association in FAS-mediated apoptosis. Apoptosis 10, 941–947. PubMed

Fan, F. , Samuel, S. , Evans, K.W. , Lu, J. , Xia, L. , Zhou, Y. , Sceusi, E. , Tozzi, F. , Ye, X.C. , Mani, S.A. , Ellis, L.M. , 2012. Overexpression of snail induces epithelial-mesenchymal transition and a cancer stem cell-like phenotype in human colorectal cancer cells. Cancer Med. 1, 5–16. PubMed PMC

Funke, S. , Timofeeva, M. , Risch, A. , Hoffmeister, M. , Stegmaier, C. , Seiler, C.M. , Brenner, H. , Chang-Claude, J. , 2010. Genetic polymorphisms in GST genes and survival of colorectal cancer patients treated with chemotherapy. Pharmacogenomics 11, 33–41. PubMed

Gagnon, V. , Mathieu, I. , Sexton, E. , Leblanc, K. , Asselin, E. , 2004. AKT involvement in cisplatin chemoresistance of human uterine cancer cells. Gynecol. Oncol 94, 785–795. PubMed

Gallagher, D.J. , Kemeny, N. , 2010. Metastatic colorectal cancer: from improved survival to potential cure. Oncology 78, 237–248. PubMed

Goldberg, R.M. , Sargent, D.J. , Morton, R.F. , Fuchs, C.S. , Ramanathan, R.K. , Williamson, S.K. , Findlay, B.P. , Pitot, H.C. , Alberts, S.R. , 2004. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J. Clin. Oncol. 22, 23–30. PubMed

Hanahan, D. , Weinberg, R.A. , 2000. The hallmarks of cancer. Cell 100, 57–70. PubMed

Hanahan, D. , Weinberg, R.A. , 2011. Hallmarks of cancer: the next generation. Cell 144, 646–674. PubMed

Hoshino, H. , Miyoshi, N. , Nagai, K. , Tomimaru, Y. , Nagano, H. , Sekimoto, M. , Doki, Y. , Mori, M. , Ishii, H. , 2009. Epithelial-mesenchymal transition with expression of SNAI1-induced chemoresistance in colorectal cancer. Biochem. Biophys. Res. Commun. 390, 1061–1065. PubMed

Hsiang, Y.H. , Liu, L.F. , 1988. Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res. 48, 1722–1726. PubMed

Huang, d.W. , Sherman, B.T. , Lempicki, R.A. , 2009. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 37, 1–13. PubMed PMC

Huang, d.W. , Sherman, B.T. , Lempicki, R.A. , 2009. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 4, 44–57. PubMed

Huang, S. , Holzel, M. , Knijnenburg, T. , Schlicker, A. , Roepman, P. , McDermott, U. , Garnett, M. , Grernrum, W. , Sun, C. , Prahallad, A. , Groenendijk, F.H. , Mittempergher, L. , Nijkamp, W. , Neefjes, J. , Salazar, R. , Ten, D.P. , Uramoto, H. , Tanaka, F. , Beijersbergen, R.L. , Wessels, L.F. , Bernards, R. , 2012. MED12 controls the response to multiple cancer drugs through regulation of TGF-beta receptor signaling. Cell 151, 937–950. PubMed PMC

Hwang, W.L. , Yang, M.H. , Tsai, M.L. , Lan, H.Y. , Su, S.H. , Chang, S.C. , Teng, H.W. , Yang, S.H. , Lan, Y.T. , Chiou, S.H. , Wang, H.W. , 2011. SNAIL regulates interleukin-8 expression, stem cell-like activity, and tumorigenicity of human colorectal carcinoma cells. Gastroenterology 141, 279–291. PubMed

Jensen, N.F. , Smith, D.H. , Nygard, S.B. , Romer, M.U. , Nielsen, K.V. , Brunner, N. , 2012. Predictive biomarkers with potential of converting conventional chemotherapy to targeted therapy in patients with metastatic colorectal cancer. Scand. J. Gastroenterol. 47, 340–355. PubMed

Kim, J.C. , Roh, S.A. , Cho, D.H. , Kim, T.W. , Yoon, S.N. , Kim, C.W. , Yu, C.S. , Kim, S.Y. , Kim, Y.S. , 2009. Chemoresponsiveness associated with canonical molecular changes in colorectal adenocarcinomas. Anticancer Res. 29, 3115–3123. PubMed

Koopman, M. , Venderbosch, S. , Nagtegaal, I.D. , van Krieken, J.H. , Punt, C.J. , 2009. A review on the use of molecular markers of cytotoxic therapy for colorectal cancer, what have we learned?. Eur. J. Cancer 45, 1935–1949. PubMed

Lao, V.V. , Grady, W.M. , 2011. Epigenetics and colorectal cancer. Nat. Rev. Gastroenterol. Hepatol. 8, 686–700. PubMed PMC

Lecomte, T. , Landi, B. , Beaune, P. , Laurent-Puig, P. , Loriot, M.A. , 2006. Glutathione S-transferase P1 polymorphism (Ile105Val) predicts cumulative neuropathy in patients receiving oxaliplatin-based chemotherapy. Clin. Cancer Res. 12, 3050–3056. PubMed

Mathieu, A. , Remmelink, M. , D'Haene, N. , Penant, S. , Gaussin, J.F. , Van, G.R. , Darro, F. , Kiss, R. , Salmon, I. , 2004. Development of a chemoresistant orthotopic human nonsmall cell lung carcinoma model in nude mice: analyses of tumor heterogenity in relation to the immunohistochemical levels of expression of cyclooxygenase-2, ornithine decarboxylase, lung-related resistance protein, prostaglandin E synthetase, and glutathione-S-transferase-alpha (GST)-alpha, GST-mu, and GST-pi. Cancer 101, 1908–1918. PubMed

Monte, M. , Simonatto, M. , Peche, L.Y. , Bublik, D.R. , Gobessi, S. , Pierotti, M.A. , Rodolfo, M. , Schneider, C. , 2006. MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents. Proc. Natl. Acad. Sci. U. S. A. 103, 11160–11165. PubMed PMC

National Comprehensive Cancer, N, 2013. NCCN Guidelines Version 3.2013 Colon Cancer (cited 2013 June 10) National Comprehensive Cancer Network; Available from: http://nccn.org/professionals/physician_gls/f_guidelines.asp

Novotna, R. , Wsol, V. , Xiong, G. , Maser, E. , 2008. Inactivation of the anticancer drugs doxorubicin and oracin by aldo-keto reductase (AKR) 1C3. Toxicol. Lett. 181, 1–6. PubMed

Oliveros, J.C. , 2007. VENNY. An Interactive Tool for Comparing lists with Venn Diagrams http://bioinfogp.cnb.csic.es/tools/venny/index.html

Penning, T.M. , Byrns, M.C. , 2009. Steroid hormone transforming aldo-keto reductases and cancer. Ann. N. Y. Acad. Sci. 1155, 33–42. PubMed PMC

Perez-Villamil, B. , Romera-Lopez, A. , Hernandez-Prieto, S. , Lopez-Campos, G. , Calles, A. , Lopez-Asenjo, J.A. , Sanz-Ortega, J. , Fernandez-Perez, C. , Sastre, J. , Alfonso, R. , Caldes, T. , Martin-Sanchez, F. , Diaz-Rubio, E. , 2012. Colon cancer molecular subtypes identified by expression profiling and associated to stroma, mucinous type and different clinical behavior. BMC Cancer 12, 260 PubMed PMC

Petitprez, A. , Poindessous, V. , Ouaret, D. , Regairaz, M. , Bastian, G. , Guerin, E. , Escargueil, A.E. , Larsen, A.K. , 2013. Acquired irinotecan resistance is accompanied by stable modifications of cell cycle dynamics independent of MSI status. Int. J. Oncol PubMed

Pfister, T.D. , Reinhold, W.C. , Agama, K. , Gupta, S. , Khin, S.A. , Kinders, R.J. , Parchment, R.E. , Tomaszewski, J.E. , Doroshow, J.H. , Pommier, Y. , 2009. Topoisomerase I levels in the NCI-60 cancer cell line panel determined by validated ELISA and microarray analysis and correlation with indenoisoquinoline sensitivity. Mol. Cancer Ther. 8, 1878–1884. PubMed PMC

Pommier, Y. , 2009. DNA topoisomerase I inhibitors: chemistry, biology, and interfacial inhibition. Chem. Rev. 109, 2894–2902. PubMed PMC

Popovici, V. , Budinska, E. , Bosman, F.T. , Tejpar, S. , Roth, A.D. , Delorenzi, M. , 2013. Context-dependent interpretation of the prognostic value of BRAF and KRAS mutations in colorectal cancer. BMC Cancer 13, 439 PubMed PMC

Popovici, V. , Budinska, E. , Tejpar, S. , Weinrich, S. , Estrella, H. , Hodgson, G. , van, C.E. , Xie, T. , Bosman, F.T. , Roth, A.D. , Delorenzi, M. , 2012. Identification of a poor-prognosis BRAF-mutant-like population of patients with colon cancer. J. Clin. Oncol 30, 1288–1295. PubMed

Qvortrup, C. , Jensen, B.V. , Fokstuen, T. , Nielsen, S.E. , Keldsen, N. , Glimelius, B. , Bjerregaard, B. , Mejer, J. , Larsen, F.O. , Pfeiffer, P. , 2010. A randomized study comparing short-time infusion of oxaliplatin in combination with capecitabine XELOX(30) and chronomodulated XELOX(30) as first-line therapy in patients with advanced colorectal cancer. Ann. Oncol. 21, 87–91. PubMed

Rabik, C.A. , Dolan, M.E. , 2007. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat. Rev. 33, 9–23. PubMed PMC

Rasheed, Z.A. , Rubin, E.H. , 2003. Mechanisms of resistance to topoisomerase I-targeting drugs. Oncogene 22, 7296–7304. PubMed

Rasmussen, M.H. , Jensen, N.F. , Tarpgaard, L.S. , Qvortrup, C. , Romer, M.U. , Stenvang, J. , Hansen, T.P. , Christensen, L.L. , Lindebjerg, J. , Hansen, F. , Jensen, B.V. , Hansen, T.F. , Pfeiffer, P. , Brunner, N. , Orntoft, T.F. , Andersen, C.L. , 2013. High expression of microRNA-625-3p is associated with poor response to first-line oxaliplatin based treatment of metastatic colorectal cancer. Mol. Oncol. 7, 637–646. PubMed PMC

Redmond, K.M. , Wilson, T.R. , Johnston, P.G. , Longley, D.B. , 2008. Resistance mechanisms to cancer chemotherapy. Front Biosci. 13, 5138–5154. PubMed

Robey, R.W. , Massey, P.R. , Amiri-Kordestani, L. , Bates, S.E. , 2010. ABC transporters: unvalidated therapeutic targets in cancer and the CNS. Anticancer Agents Med. Chem. 10, 625–633. PubMed PMC

Ross, D. , Nakanishi, T. , 2010. Impact of breast Cancer resistance protein on Cancer treatment outcomes. In Zhou J., Multi-drug Resistance in Cancer Humana Press; 251–290. PubMed

Roth, A.D. , Tejpar, S. , Delorenzi, M. , Yan, P. , Fiocca, R. , Klingbiel, D. , Dietrich, D. , Biesmans, B. , Bodoky, G. , Barone, C. , Aranda, E. , Nordlinger, B. , Cisar, L. , Labianca, R. , Cunningham, D. , Van Cutsem, E. , Bosman, F. , 2010. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 28, 466–474. PubMed

Sadanandam, A. , Lyssiotis, C.A. , Homicsko, K. , Collisson, E.A. , Gibb, W.J. , Wullschleger, S. , Ostos, L.C. , Lannon, W.A. , Grotzinger, C. , Del Rio, M. , Lhermitte, B. , Olshen, A.B. , Wiedenmann, B. , Cantley, L.C. , Gray, J.W. , Hanahan, D. , 2013. A colorectal cancer classification system that associates cellular phenotype and responses to therapy. Nat. Med. 19, 619–625. PubMed PMC

Saeed, A.I. , Bhagabati, N.K. , Braisted, J.C. , Liang, W. , Sharov, V. , Howe, E.A. , Li, J. , Thiagarajan, M. , White, J.A. , Quackenbush, J. , 2006. TM4 microarray software suite. Methods Enzymol. 411, 134–193. PubMed

Santoni, G. , Farfariello, V. , 2011. TRP channels and cancer: new targets for diagnosis and chemotherapy. Endocr. Metab. Immune. Disord. Drug Targets 11, 54–67. PubMed

Saxena, M. , Stephens, M.A. , Pathak, H. , Rangarajan, A. , 2011. Transcription factors that mediate epithelial-mesenchymal transition lead to multidrug resistance by upregulating ABC transporters. Cell Death. Dis. 2, e179 PubMed PMC

Scurr, L.L. , Guminski, A.D. , Chiew, Y.E. , Balleine, R.L. , Sharma, R. , Lei, Y. , Pryor, K. , Wain, G.V. , Brand, A. , Byth, K. , Kennedy, C. , Rizos, H. , Harnett, P.R. , deFazio, A. , 2008. Ankyrin repeat domain 1, ANKRD1, a novel determinant of cisplatin sensitivity expressed in ovarian cancer. Clin. Cancer Res. 14, 6924–6932. PubMed

Silvestris, N. , Simone, G. , Partipilo, G. , Scarpi, E. , Lorusso, V. , Brunetti, A.E. , Maiello, E. , Paradiso, A. , Mangia, A. , 2014. CES2, ABCG2, TS and Topo-I primary and synchronous metastasis expression and clinical outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI regimen. Int. J. Mol. Sci. 15, 15767–15777. PubMed PMC

Simons, C.C. , Hughes, L.A. , Smits, K.M. , Khalid-de Bakker, C.A. , de Bruine, A.P. , Carvalho, B. , Meijer, G.A. , Schouten, L.J. , van den Brandt, P.A. , Weijenberg, M.P. , van Engeland, M. , 2013. A novel classification of colorectal tumors based on microsatellite instability, the CpG island methylator phenotype and chromosomal instability: implications for prognosis. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol./ESMO 24, 2048–2056. PubMed

Singh, A. , Settleman, J. , 2010. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29, 4741–4751. PubMed PMC

Smyth, G.K. , 2005. Limma: linear models for microarray data. In Gentleman R., Carey V., Dudoit S., Irizarry R., Huber W.(Eds.), Bioinformatics and Computational Biology Solutions using R and Bioconductor Springer; New York: 397–420.

Suzuki, T. , Yoshida, K. , Wada, Y. , Hamai, Y. , Sentani, K. , Oue, N. , Yasui, W. , 2007. Melanoma-associated antigen-A1 expression predicts resistance to docetaxel and paclitaxel in advanced and recurrent gastric cancer. Oncol. Rep. 18, 329–336. PubMed

Tai, I.T. , Dai, M. , Owen, D.A. , Chen, L.B. , 2005. Genome-wide expression analysis of therapy-resistant tumors reveals SPARC as a novel target for cancer therapy. J. Clin. Invest. 115, 1492–1502. PubMed PMC

Thomas, P.D. , Kejariwal, A. , Campbell, M.J. , Mi, H. , Diemer, K. , Guo, N. , Ladunga, I. , Ulitsky-Lazareva, B. , Muruganujan, A. , Rabkin, S. , Vandergriff, J.A. , Doremieux, O. , 2003. PANTHER: a browsable database of gene products organized by biological function, using curated protein family and subfamily classification. Nucleic Acids Res. 31, 334–341. PubMed PMC

Tournigand, C. , Andre, T. , Achille, E. , Lledo, G. , Flesh, M. , Mery-Mignard, D. , Quinaux, E. , Couteau, C. , Buyse, M. , Ganem, G. , Landi, B. , Colin, P. , Louvet, C. , de Gramont, A. , 2004. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 22, 229–237. PubMed

van Cutsem, E. , Labianca, R. , Bodoky, G. , Barone, C. , Aranda, E. , Nordlinger, B. , Topham, C. , Tabernero, J. , Andre, T. , Sobrero, A.F. , Mini, E. , Greil, R. , Di, C.F. , Collette, L. , Cisar, L. , Zhang, X. , Khayat, D. , Bokemeyer, C. , Roth, A.D. , Cunningham, D. , 2009. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J. Clin. Oncol 27, 3117–3125. PubMed

van Loevezijn, A. , Allen, J.D. , Schinkel, A.H. , Koomen, G.J. , 2001. Inhibition of BCRP-mediated drug efflux by fumitremorgin-type indolyl diketopiperazines. Bioorg. Med. Chem. Lett. 11, 29–32. PubMed

Veitch, Z.W. , Guo, B. , Hembruff, S.L. , Bewick, A.J. , Heibein, A.D. , Eng, J. , Cull, S. , Maclean, D.A. , Parissenti, A.M. , 2009. Induction of 1C aldoketoreductases and other drug dose-dependent genes upon acquisition of anthracycline resistance. Pharmacogenet. Genomics 19, 477–488. PubMed

Voulgari, A. , Pintzas, A. , 2009. Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim. Biophys. Acta 1796, 75–90. PubMed

Walther, A. , Johnstone, E. , Swanton, C. , Midgley, R. , Tomlinson, I. , Kerr, D. , 2009. Genetic prognostic and predictive markers in colorectal cancer. Nat. Rev. Cancer 9, 489–499. PubMed

Wu, C.P. , Hsieh, C.H. , Wu, Y.S. , 2011. The emergence of drug transporter-mediated multidrug resistance to cancer chemotherapy. Mol. Pharm. 8, 1996–2011. PubMed

Wu, K.L. , Khan, S. , Lakhe-Reddy, S. , Jarad, G. , Mukherjee, A. , Obejero-Paz, C.A. , Konieczkowski, M. , Sedor, J.R. , Schelling, J.R. , 2004. The NHE1 Na+/H+ exchanger recruits ezrin/radixin/moesin proteins to regulate Akt-dependent cell survival. J. Biol. Chem. 279, 26280–26286. PubMed

Yang, A.D. , Fan, F. , Camp, E.R. , van, B.G. , Liu, W. , Somcio, R. , Gray, M.J. , Cheng, H. , Hoff, P.M. , Ellis, L.M. , 2006. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin. Cancer Res. 12, 4147–4153. PubMed

Zamble, D.B. , Mu, D. , Reardon, J.T. , Sancar, A. , Lippard, S.J. , 1996. Repair of cisplatin–DNA adducts by the mammalian excision nuclease. Biochemistry 35, 10004–10013. PubMed

Zhong, L. , Shen, H. , Huang, C. , Jing, H. , Cao, D. , 2011. AKR1B10 induces cell resistance to daunorubicin and idarubicin by reducing C13 ketonic group. Toxicol. Appl. Pharmacol. 255, 40–47. PubMed PMC

Zhou, Q. , Sparreboom, A. , Tan, E.H. , Cheung, Y.B. , Lee, A. , Poon, D. , Lee, E.J. , Chowbay, B. , 2005. Pharmacogenetic profiling across the irinotecan pathway in Asian patients with cancer. Br. J. Clin. Pharmacol. 59, 415–424. PubMed PMC

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