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6-Thioguanine Selectively Kills BRCA2-Defective Tumors and Overcomes PARP Inhibitor Resistance
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för genetik, mikrobiologi och toxikologi.
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2010 (Engelska)Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 70, nr 15, s. 6268-6276Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Familial breast and ovarian cancers are often defective in homologous recombination (HR) due to mutations in the BRCA1 or BRCA2 genes. Cisplatin chemotherapy or poly(ADP-ribose) polymerase (PARP) inhibitors were tested for these tumors in clinical trials. In a screen for novel drugs that selectively kill BRCA2-defective cells, we identified 6-thioguanine (6TG), which induces DNA double-strand breaks (DSB) that are repaired by HR. Furthermore, we show that 6TG is as efficient as a PARP inhibitor in selectively killing BRCA2-defective tumors in a xenograft model. Spontaneous BRCA1-defective mammary tumors gain resistance to PARP inhibitors through increased P-glycoprotein expression. Here, we show that 6TG efficiently kills such BRCA1-defective PARP inhibitor-resistant tumors. We also show that 6TG could kill cells and tumors that have gained resistance to PARP inhibitors or cisplatin through genetic reversion of the BRCA2 gene. Although HR is reactivated in PARP inhibitor-resistant BRCA2-defective cells, it is not fully restored for the repair of 6TG-induced lesions. This is likely to be due to several recombinogenic lesions being formed after 6TG. We show that BRCA2 is also required for survival from mismatch repair-independent lesions formed by 6TG, which do not include DSBs. This suggests that HR is involved in the repair of 6TG-induced DSBs as well as mismatch repair-independent 6TG-induced DNA lesion. Altogether, our data show that 6TG efficiently kills BRCA2-defective tumors and suggest that 6TG may be effective in the treatment of advanced tumors that have developed resistance to PARP inhibitors or platinum-based chemotherapy. Cancer Res; 70(15); 6268-76. (C) 2010 AACR.

Ort, förlag, år, upplaga, sidor
2010. Vol. 70, nr 15, s. 6268-6276
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylärgenetik
Identifikatorer
URN: urn:nbn:se:su:diva-49721DOI: 10.1158/0008-5472.CAN-09-3416ISI: 000280557500017OAI: oai:DiVA.org:su-49721DiVA, id: diva2:379193
Anmärkning

authorCount :20

Tillgänglig från: 2010-12-17 Skapad: 2010-12-17 Senast uppdaterad: 2017-12-11Bibliografiskt granskad
Ingår i avhandling
1. Interplay between Transcription and Homologous Recombination in the Presence of DNA Damage
Öppna denna publikation i ny flik eller fönster >>Interplay between Transcription and Homologous Recombination in the Presence of DNA Damage
2011 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

The biochemical processes of DNA repair, replication and recombination compete for the same substrate, the DNA molecule. This competition is natural, as each process requires the same template. In order to resolve possible conflicts between these processes, when they take place on a particular stretch of DNA, certain crosstalk is expected. The complexity is additionally increased by the existence of another DNA dependent process, which occurs in all phases of the cell cycle: transcription.

This thesis aims to investigate the link between transcription inhibition and homologous recombination, especially in the context of UV-induced DNA damage. The results show that the transcription inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) induces homologous recombination. The DNA damage caused by UVC irradiation is repaired mainly via nucleotide excision repair, however, it is also known to trigger recombinational repair. In the presence of UV-induced damage, transcription inhibition by DRB potentiates the induction of homologous recombination as a necessary mechanism of cell survival.

The thesis also focuses on the toxicity mechanisms of the chemotherapeutic compound 6-thioguanine (6TG). The work in the thesis suggests application of 6TG as a treatment for hereditary forms of breast cancer, with genetically altered BRCA1 or BRCA2 functions. Most importantly, the treatment with 6TG is applicable to breast cancers, which have developed resistance to another class of chemotherapeutic drugs, poly-(ADP-ribose) polymerase (PARP) inhibitors. Repair of the DNA damage induced by 6TG treatment is investigated further with a particular focus the pathway of DNA damage avoidance involving DNA polymerase η. The function of DNA polymerase η seems to be an important factor for the outcome of DNA repair after 6TG exposure. The deficiency of DNA polymerase η is also investigated in connection with normal replication and the repair of UV-induced DNA damage.

In summary, the work in the thesis sheds more light onto the fundamental connections between DNA replication, recombination, transcription, repair and damage avoidance. On a more practical side, the information obtained about these fundamental connections is used to suggest a possible therapy for several forms of breast cancer.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Genetics, Microbiology and Toxicology, Stockholm University, 2011. s. 70
Nyckelord
homologous recombination, transcription, DRB, UVC, 6-thioguanine, mammalian cells, BRCA1, BRCA2, PARP inhibitors, XP-V
Nationell ämneskategori
Biokemi och molekylärbiologi
Forskningsämne
molekylärgenetik
Identifikatorer
urn:nbn:se:su:diva-54736 (URN)978-91-7447-217-2 (ISBN)
Disputation
2011-03-18, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 13:00 (Engelska)
Opponent
Handledare
Anmärkning
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript. Paper 5: Manuscript.Tillgänglig från: 2011-02-24 Skapad: 2011-02-14 Senast uppdaterad: 2011-02-16Bibliografiskt granskad

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Av författaren/redaktören
Stoimenov, IvayloChatzakos, VickyGubanova, EvgeniaHelleday, Thomas
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Institutionen för genetik, mikrobiologi och toxikologi
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Cancer Research
Biokemi och molekylärbiologi

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