publication . Article . 2013

Inhibition of BRCA2 and Thymidylate Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined “Complementary Lethality”

Rytelewski, Mateusz; Ferguson, Peter J; Vareki, Saman Maleki; Figueredo, Rene; Vincent, Mark; Koropatnick, James;
Open Access English
  • Published: 01 Mar 2013 Journal: Molecular Therapy. Nucleic Acids, volume 2, issue 3, page e78 (issn: 2162-2531, eissn: 2162-2531, Copyright policy)
  • Publisher: Nature Publishing Group
Abstract
A high mutation rate leading to tumor cell heterogeneity is a driver of malignancy in human cancers. Paradoxically, however, genomic instability can also render tumors vulnerable to therapeutic attack. Thus, targeting DNA repair may induce an intolerable level of DNA damage in tumor cells. BRCA2 mediates homologous recombination repair, and BRCA2 polymorphisms increase cancer risk. However, tumors with BRCA2 mutations respond better to chemotherapy and are associated with improved patient prognosis. Thymidylate synthase (TS) is also involved in DNA maintenance and generates cellular thymidylate. We determined that antisense downregulation of BRCA2 synergisticall...
Subjects
free text keywords: Original Article, drug sensitivity, RM1-950, Therapeutics. Pharmacology, complementary lethality, DNA repair, BRCA2, antisense, TS
Funded by
CIHR
Project
  • Funder: Canadian Institutes of Health Research (CIHR)
50 references, page 1 of 4

Youn, A and Simon, R (2012). Estimating the order of mutations during tumorigenesis from tumor genome sequencing data. Bioinformatics 28: 1555–1561.22492649 [OpenAIRE] [PubMed]

Pleasance, ED, Cheetham, RK, Stephens, PJ, McBride, DJ, Humphray, SJ, Greenman, CD et al. (2010). A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463: 191–196.20016485 [OpenAIRE] [PubMed]

Loeb, LA (2011). Human cancers express mutator phenotypes: origin, consequences and targeting. Nat Rev Cancer 11: 450–457.21593786 [OpenAIRE] [PubMed]

Cassidy, LD an d Venkitaraman, AR (2012). Genome instability mechanisms and the structure of cancer genomes. Curr Opin Genet Dev 22: 10–13.22366532 [PubMed]

Lee, W, Jiang, Z, Liu, J, Haverty, PM, Guan, Y, Stinson, J et al. (2010). The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 465: 473–477.20505728 [PubMed]

Russnes, HG, Navin, N, Hicks, J and Borresen-Dale, AL (2011). Insight into the heterogeneity of breast cancer through next-generation sequencing. J Clin Invest 121: 3810–3818.21965338 [OpenAIRE] [PubMed]

Guo, HH, Choe, J and Loeb, LA (2004). Protein tolerance to random amino acid change. Proc Natl Acad Sci USA 101: 9205–9210.15197260 [OpenAIRE] [PubMed]

Shaheen, M, Allen, C, Nickoloff, JA and Hromas, R (2011). Synthetic lethality: exploiting the addiction of cancer to DNA repair. Blood 117: 6074–6082.21441464 [PubMed]

Holloman, WK (2011). Un raveling the mechanism of BRCA2 in homologous recombination. Nat Struct Mol Biol 18: 748–754.21731065 [OpenAIRE] [PubMed]

Carreira, A, Hilario, J, Amitani, I, Baskin, RJ, Shivji, MK, Venkitaraman, AR et al. (2009). The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51. Cell 136: 1032–1043.19303847 [OpenAIRE] [PubMed]

Wooster, R, Bignell, G, Lancaster, J, Swift, S, Seal, S, Mangion, J et al. (1995). Identification of the breast cancer susceptibility gene BRCA2. Nature 378: 789–792.8524414 [PubMed]

Tan, DS, Rothermundt, C, Thomas, K, Bancroft, E, Eeles, R, Shanley, S et al. (2008). “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 26: 5530–5536.18955455 [PubMed]

Hughes-Davies, L, Huntsman, D, Ruas, M, Fuks, F, Bye, J, Chin, SF et al. (2003). EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115: 523–535.14651845 [PubMed]

Vencken, PM, Kriege, M, Hoogwerf, D, Beugelink, S, van der Burg, ME, Hooning, MJ et al. (2011). Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 22: 1346–1352.21228333 [PubMed]

Ben David, Y, Chetrit, A, Hirsh-Yechezkel, G, Friedman, E, Beck, BD, Beller, U et al.; National Israeli Study of Ovarian Cancer. (2002). Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 20: 463–466.11786575 [PubMed]

50 references, page 1 of 4
Abstract
A high mutation rate leading to tumor cell heterogeneity is a driver of malignancy in human cancers. Paradoxically, however, genomic instability can also render tumors vulnerable to therapeutic attack. Thus, targeting DNA repair may induce an intolerable level of DNA damage in tumor cells. BRCA2 mediates homologous recombination repair, and BRCA2 polymorphisms increase cancer risk. However, tumors with BRCA2 mutations respond better to chemotherapy and are associated with improved patient prognosis. Thymidylate synthase (TS) is also involved in DNA maintenance and generates cellular thymidylate. We determined that antisense downregulation of BRCA2 synergisticall...
Subjects
free text keywords: Original Article, drug sensitivity, RM1-950, Therapeutics. Pharmacology, complementary lethality, DNA repair, BRCA2, antisense, TS
Funded by
CIHR
Project
  • Funder: Canadian Institutes of Health Research (CIHR)
50 references, page 1 of 4

Youn, A and Simon, R (2012). Estimating the order of mutations during tumorigenesis from tumor genome sequencing data. Bioinformatics 28: 1555–1561.22492649 [OpenAIRE] [PubMed]

Pleasance, ED, Cheetham, RK, Stephens, PJ, McBride, DJ, Humphray, SJ, Greenman, CD et al. (2010). A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 463: 191–196.20016485 [OpenAIRE] [PubMed]

Loeb, LA (2011). Human cancers express mutator phenotypes: origin, consequences and targeting. Nat Rev Cancer 11: 450–457.21593786 [OpenAIRE] [PubMed]

Cassidy, LD an d Venkitaraman, AR (2012). Genome instability mechanisms and the structure of cancer genomes. Curr Opin Genet Dev 22: 10–13.22366532 [PubMed]

Lee, W, Jiang, Z, Liu, J, Haverty, PM, Guan, Y, Stinson, J et al. (2010). The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 465: 473–477.20505728 [PubMed]

Russnes, HG, Navin, N, Hicks, J and Borresen-Dale, AL (2011). Insight into the heterogeneity of breast cancer through next-generation sequencing. J Clin Invest 121: 3810–3818.21965338 [OpenAIRE] [PubMed]

Guo, HH, Choe, J and Loeb, LA (2004). Protein tolerance to random amino acid change. Proc Natl Acad Sci USA 101: 9205–9210.15197260 [OpenAIRE] [PubMed]

Shaheen, M, Allen, C, Nickoloff, JA and Hromas, R (2011). Synthetic lethality: exploiting the addiction of cancer to DNA repair. Blood 117: 6074–6082.21441464 [PubMed]

Holloman, WK (2011). Un raveling the mechanism of BRCA2 in homologous recombination. Nat Struct Mol Biol 18: 748–754.21731065 [OpenAIRE] [PubMed]

Carreira, A, Hilario, J, Amitani, I, Baskin, RJ, Shivji, MK, Venkitaraman, AR et al. (2009). The BRC repeats of BRCA2 modulate the DNA-binding selectivity of RAD51. Cell 136: 1032–1043.19303847 [OpenAIRE] [PubMed]

Wooster, R, Bignell, G, Lancaster, J, Swift, S, Seal, S, Mangion, J et al. (1995). Identification of the breast cancer susceptibility gene BRCA2. Nature 378: 789–792.8524414 [PubMed]

Tan, DS, Rothermundt, C, Thomas, K, Bancroft, E, Eeles, R, Shanley, S et al. (2008). “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. J Clin Oncol 26: 5530–5536.18955455 [PubMed]

Hughes-Davies, L, Huntsman, D, Ruas, M, Fuks, F, Bye, J, Chin, SF et al. (2003). EMSY links the BRCA2 pathway to sporadic breast and ovarian cancer. Cell 115: 523–535.14651845 [PubMed]

Vencken, PM, Kriege, M, Hoogwerf, D, Beugelink, S, van der Burg, ME, Hooning, MJ et al. (2011). Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients. Ann Oncol 22: 1346–1352.21228333 [PubMed]

Ben David, Y, Chetrit, A, Hirsh-Yechezkel, G, Friedman, E, Beck, BD, Beller, U et al.; National Israeli Study of Ovarian Cancer. (2002). Effect of BRCA mutations on the length of survival in epithelial ovarian tumors. J Clin Oncol 20: 463–466.11786575 [PubMed]

50 references, page 1 of 4
Powered by OpenAIRE Open Research Graph
Any information missing or wrong?Report an Issue
publication . Article . 2013

Inhibition of BRCA2 and Thymidylate Synthase Creates Multidrug Sensitive Tumor Cells via the Induction of Combined “Complementary Lethality”

Rytelewski, Mateusz; Ferguson, Peter J; Vareki, Saman Maleki; Figueredo, Rene; Vincent, Mark; Koropatnick, James;