6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance
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.
| Errataetall: | |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2010 |
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| Erschienen: |
2010 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:70 |
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| Enthalten in: |
Cancer research - 70(2010), 15 vom: 01. Aug., Seite 6268-76 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Issaeva, Natalia [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 13.09.2010 Date Revised 20.10.2021 published: Print-Electronic ErratumIn: Cancer Res. 2010 Oct 1;70(19):7734 Djurenovic, Tatjana [corrected to Djureinovic, Tatjana] Citation Status MEDLINE |
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| doi: |
10.1158/0008-5472.CAN-09-3416 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 100 | 1 | |a Issaeva, Natalia |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a 6-thioguanine selectively kills BRCA2-defective tumors and overcomes PARP inhibitor resistance |
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| 500 | |a Date Completed 13.09.2010 | ||
| 500 | |a Date Revised 20.10.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ErratumIn: Cancer Res. 2010 Oct 1;70(19):7734 Djurenovic, Tatjana [corrected to Djureinovic, Tatjana] | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
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| 650 | 7 | |a Antimetabolites, Antineoplastic |2 NLM | |
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| 700 | 1 | |a Thomas, Huw D |e verfasserin |4 aut | |
| 700 | 1 | |a Djureinovic, Tatjana |e verfasserin |4 aut | |
| 700 | 1 | |a Djurenovic, Tatjana |e verfasserin |4 aut | |
| 700 | 1 | |a Jaspers, Janneke E |e verfasserin |4 aut | |
| 700 | 1 | |a Stoimenov, Ivaylo |e verfasserin |4 aut | |
| 700 | 1 | |a Kyle, Suzanne |e verfasserin |4 aut | |
| 700 | 1 | |a Pedley, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Gottipati, Ponnari |e verfasserin |4 aut | |
| 700 | 1 | |a Zur, Rafal |e verfasserin |4 aut | |
| 700 | 1 | |a Sleeth, Kate |e verfasserin |4 aut | |
| 700 | 1 | |a Chatzakos, Vicky |e verfasserin |4 aut | |
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| 700 | 1 | |a Lundin, Cecilia |e verfasserin |4 aut | |
| 700 | 1 | |a Gubanova, Evgenia |e verfasserin |4 aut | |
| 700 | 1 | |a Kersbergen, Ariena |e verfasserin |4 aut | |
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| 700 | 1 | |a Curtin, Nicola J |e verfasserin |4 aut | |
| 700 | 1 | |a Helleday, Thomas |e verfasserin |4 aut | |
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