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.
Issaeva
Natalia
N
Department of Genetics, Microbiology, and Toxicology, Stockholm University, Stockholm, Sweden.
Thomas
Huw D
HD
Djureinovic
Tatjana
T
Djurenovic
Tatjana
T
Jaspers
Janneke E
JE
Stoimenov
Ivaylo
I
Kyle
Suzanne
S
Pedley
Nicholas
N
Gottipati
Ponnari
P
Zur
Rafal
R
Sleeth
Kate
K
Chatzakos
Vicky
V
Mulligan
Evan A
EA
Lundin
Cecilia
C
Gubanova
Evgenia
E
Kersbergen
Ariena
A
Harris
Adrian L
AL
Sharma
Ricky A
RA
Rottenberg
Sven
S
Curtin
Nicola J
NJ
Helleday
Thomas
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D024682:BRCA2 Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D020137:Base Pair Mismatch; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D004260:DNA Repair; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D024522:Genes, BRCA2; D045325:HCT116 Cells; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013866:Thioguanine / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C106711:BRCA2 protein, mouse; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013866:Thioguanine