@article{Xu:2017:10.1038/ncomms14432,
author = {Xu, H and Di, Antonio M and McKinney, S and Mathew, V and Ho, B and O'Neil, NJ and Dos, Santos N and Silvester, J and Wei, V and Garcia, J and Kabeer, F and Lai, D and Soriano, P and Banath, J and Chiu, DS and Yap, D and Le, DD and Ye, FB and Zhang, A and Thu, K and Soong, J and Lin, S-C and Tsai, AHC and Osako, T and Algara, T and Saunders, DN and Wong, J and Xian, J and Bally, MB and Brenton, JD and Brown, GW and Shah, SP and Cescon, D and Mak, TW and Caldas, C and Stirling, PC and Hieter, P and Balasubramanian, S and Aparicio, S},
doi = {10.1038/ncomms14432},
journal = {Nature Communications},
pages = {1--18},
title = {CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours},
url = {http://dx.doi.org/10.1038/ncomms14432},
volume = {8},
year = {2017}
}

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TY  - JOUR
AB  - G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016).
AU  - Xu,H
AU  - Di,Antonio M
AU  - McKinney,S
AU  - Mathew,V
AU  - Ho,B
AU  - O'Neil,NJ
AU  - Dos,Santos N
AU  - Silvester,J
AU  - Wei,V
AU  - Garcia,J
AU  - Kabeer,F
AU  - Lai,D
AU  - Soriano,P
AU  - Banath,J
AU  - Chiu,DS
AU  - Yap,D
AU  - Le,DD
AU  - Ye,FB
AU  - Zhang,A
AU  - Thu,K
AU  - Soong,J
AU  - Lin,S-C
AU  - Tsai,AHC
AU  - Osako,T
AU  - Algara,T
AU  - Saunders,DN
AU  - Wong,J
AU  - Xian,J
AU  - Bally,MB
AU  - Brenton,JD
AU  - Brown,GW
AU  - Shah,SP
AU  - Cescon,D
AU  - Mak,TW
AU  - Caldas,C
AU  - Stirling,PC
AU  - Hieter,P
AU  - Balasubramanian,S
AU  - Aparicio,S
DO  - 10.1038/ncomms14432
EP  - 18
PY  - 2017///
SN  - 2041-1723
SP  - 1
TI  - CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours
T2  - Nature Communications
UR  - http://dx.doi.org/10.1038/ncomms14432
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000394245100001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://www.nature.com/articles/ncomms14432#Abs1
UR  - http://hdl.handle.net/10044/1/85930
VL  - 8
ER  - 

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