Association of SUMO1 and UBC9 genotypes with tumor response in non-small-cell lung cancer treated with irinotecan-based chemotherapy

Irinotecan induces small ubiquitin-like modifier (SUMO)-1 conjugation to topoisomerase-I, leading to enhanced sensitivity to irinotecan. In this study, we genotyped SUMO1 and UBC9 polymorphisms in 147 non-small-cell lung cancer (NSCLC) treated with irinotecan chemotherapy to investigate the association between genotypes and tumor response rate. Immunohistochemistry for SUMO1 and UBC9 was performed in 42 tumor samples and correlated with genotypes. The UBC9 10920CG genotype was associated with significantly higher response rate than the C/C genotype (81 vs 37%, P=0.0002). This predictive effect on tumor response was also seen in multivariate analysis (odds ratio=8.5, P=0.003). Moreover, tumors arising from the UBC9 10920CG genotype were associated with higher prevalence of SUMO1 overexpression compared with those with CC genotype (78 vs 31%, P=0.021). This finding suggests that the UBC9 10920CG genotype enhances sensitivity to irinotecan chemotherapy in advanced NSCLC through upregulation of SUMO1 in tumor cells.

[1]  J. Barrett,et al.  Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  N. Park,et al.  Interleukin-12 p40 gene (IL12B) polymorphisms and the risk of cervical cancer in Korean women. , 2008, European journal of obstetrics, gynecology, and reproductive biology.

[3]  Joseph G Ibrahim,et al.  UGT1A1*28 genotype and irinotecan-induced neutropenia: dose matters. , 2007, Journal of the National Cancer Institute.

[4]  F. Melchior,et al.  Concepts in sumoylation: a decade on , 2007, Nature Reviews Molecular Cell Biology.

[5]  M. Bjornsti,et al.  Defects in SUMO (Small Ubiquitin-related Modifier) Conjugation and Deconjugation Alter Cell Sensitivity to DNA Topoisomerase I-induced DNA Damage* , 2005, Journal of Biological Chemistry.

[6]  Teruhiko Yoshida,et al.  Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan , 2003 .

[7]  Y. Pommier,et al.  Reduced Expression of DNA Topoisomerase I in SF295 Human Glioblastoma Cells Selected for Resistance to Homocamptothecin and Diflomotecan , 2008, Molecular Pharmacology.

[8]  E. Shin,et al.  Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  E. Rubin,et al.  Mechanisms of resistance to topoisomerase I-targeting drugs , 2003, Oncogene.

[10]  Y. Mo,et al.  Nucleolar Delocalization of Human Topoisomerase I in Response to Topotecan Correlates with Sumoylation of the Protein* , 2002, The Journal of Biological Chemistry.

[11]  A. Hengstermann,et al.  Activation of p53 by conjugation to the ubiquitin‐like protein SUMO‐1 , 1999, The EMBO journal.

[12]  P. D'Arpa,et al.  Ubiquitin-dependent Destruction of Topoisomerase I Is Stimulated by the Antitumor Drug Camptothecin* , 1997, The Journal of Biological Chemistry.

[13]  P. Elliott,et al.  Enhanced chemosensitivity to CPT-11 with proteasome inhibitor PS-341: implications for systemic nuclear factor-kappaB inhibition. , 2001, Cancer research.

[14]  J. Verweij,et al.  Irinotecan‐induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein , 2007, Clinical pharmacology and therapeutics.

[15]  Yves Pommier,et al.  Topoisomerase I inhibitors: selectivity and cellular resistance. , 1999, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[16]  Soma Das,et al.  Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[17]  L. Liu,et al.  SUMO-1 conjugation to topoisomerase I: A possible repair response to topoisomerase-mediated DNA damage. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Y. Taketani,et al.  SUMO-1 conjugation to intact DNA topoisomerase I amplifies cleavable complex formation induced by camptothecin , 2002, Oncogene.

[19]  Ji-Youn Han,et al.  Integrated pharmacogenetic prediction of irinotecan pharmacokinetics and toxicity in patients with advanced non-small cell lung cancer. , 2009, Lung cancer.

[20]  R. Hay,et al.  SUMO‐1 modification activates the transcriptional response of p53 , 1999, The EMBO journal.

[21]  Y. Pommier.  Topoisomerase I inhibitors: camptothecins and beyond , 2006, Nature Reviews Cancer.

[22]  T. Tsuruo,et al.  Decreased expression of DNA topoisomerase I in camptothecin-resistant tumor cell lines as determined by a monoclonal antibody. , 1990, Cancer research.

[23]  E. Shin,et al.  Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan‐pharmacokinetics and clinical outcome in patients with advanced non‐small cell lung cancer , 2007, Cancer.

[24]  Jaulang Hwang,et al.  Assembly of a Polymeric Chain of SUMO1 on Human Topoisomerase I in Vitro* , 2006, Journal of Biological Chemistry.

[25]  E. Shimizu,et al.  Severe toxicities after irinotecan-based chemotherapy in a patient with lung cancer: a homozygote for the SLCO1B1*15 allele. , 2007, Therapeutic drug monitoring.

[26]  J. Schellens,et al.  Platinated DNA Adducts Enhance Poisoning of DNA Topoisomerase I by Camptothecin* , 2004, Journal of Biological Chemistry.

[27]  S. Fukushima,et al.  Involvement of ubiquitination and sumoylation in bladder lesions induced by persistent long-term low dose ionizing radiation in humans. , 2006, The Journal of urology.

[28]  Y. Mo,et al.  Overexpression of a dominant-negative mutant Ubc9 is associated with increased sensitivity to anticancer drugs. , 2004, Cancer research.

[29]  R. Hay,et al.  Ubch9 conjugates SUMO but not ubiquitin , 1997, FEBS letters.

[30]  R. Hay,et al.  SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. , 1998, Molecular cell.

[31]  M. Villalona-Calero,et al.  Irinotecan: mechanisms of tumor resistance and novel strategies for modulating its activity. , 2002, Annals of oncology : official journal of the European Society for Medical Oncology.