CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours

Hong Xu; Marco Di Antonio; Steven McKinney; Veena Mathew; Brandon Ho; Nigel J. O'Neil; Nancy Dos Santos; Jennifer Silvester; Vivien Wei; Jessica Garcia; Farhia Kabeer; Daniel Lai; Priscilla Soriano; Judit Banáth; Derek S. Chiu; Damian Yap; Daniel D. Le; Frank B. Ye; Anni Zhang; Kelsie Thu; John Soong; Shu Chuan Lin; Angela Hsin Chin Tsai; Tomo Osako; Teresa Algara; Darren N. Saunders; Jason Wong; Jian Xian; Marcel B. Bally; James D. Brenton; Grant W. Brown; Sohrab P. Shah; David Cescon; Tak W. Mak; Carlos Caldas; Peter C. Stirling; Phil Hieter; Shankar Balasubramanian; Samuel Aparicio

doi:10.1038/ncomms14432

CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours

Hong Xu
, Marco Di Antonio
, Steven McKinney
, Veena Mathew
, Brandon Ho
, Nigel J. O'Neil
, Nancy Dos Santos
, Jennifer Silvester
, Vivien Wei
, Jessica Garcia
, Farhia Kabeer
, Daniel Lai
, Priscilla Soriano
, Judit Banáth
, Derek S. Chiu
, Damian Yap
, Daniel D. Le
, Frank B. Ye
, Anni Zhang
, Kelsie Thu

John Soong, Shu Chuan Lin, Angela Hsin Chin Tsai, Tomo Osako, Teresa Algara, Darren N. Saunders, Jason Wong, Jian Xian, Marcel B. Bally, James D. Brenton, Grant W. Brown, Sohrab P. Shah, David Cescon, Tak W. Mak, Carlos Caldas, Peter C. Stirling, Phil Hieter, Shankar Balasubramanian, Samuel Aparicio^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

501 Scopus citations

Abstract

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).

Original language	English
Article number	14432
Journal	Nature Communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms14432
State	Published - 17 Feb 2017
Externally published	Yes

Bibliographical note

Publisher Copyright:
© The Author(s) 2017.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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Xu, H., Di Antonio, M., McKinney, S., Mathew, V., Ho, B., O'Neil, N. J., Santos, N. D., Silvester, J., Wei, V., Garcia, J., Kabeer, F., Lai, D., Soriano, P., Banáth, J., Chiu, D. S., Yap, D., Le, D. D., Ye, F. B., Zhang, A., ... Aparicio, S. (2017). CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours. Nature Communications, 8, Article 14432. https://doi.org/10.1038/ncomms14432

@article{37cf067bc2dd4ccfb79f7ec7e43f1ca0,

title = "CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours",

abstract = "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).",

author = "Hong Xu and \{Di Antonio\}, Marco and Steven McKinney and Veena Mathew and Brandon Ho and O'Neil, \{Nigel J.\} and Santos, \{Nancy Dos\} and Jennifer Silvester and Vivien Wei and Jessica Garcia and Farhia Kabeer and Daniel Lai and Priscilla Soriano and Judit Ban{\'a}th and Chiu, \{Derek S.\} and Damian Yap and Le, \{Daniel D.\} and Ye, \{Frank B.\} and Anni Zhang and Kelsie Thu and John Soong and Lin, \{Shu Chuan\} and Tsai, \{Angela Hsin Chin\} and Tomo Osako and Teresa Algara and Saunders, \{Darren N.\} and Jason Wong and Jian Xian and Bally, \{Marcel B.\} and Brenton, \{James D.\} and Brown, \{Grant W.\} and Shah, \{Sohrab P.\} and David Cescon and Mak, \{Tak W.\} and Carlos Caldas and Stirling, \{Peter C.\} and Phil Hieter and Shankar Balasubramanian and Samuel Aparicio",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2017.",

year = "2017",

month = feb,

day = "17",

doi = "10.1038/ncomms14432",

language = "אנגלית",

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Xu, H, Di Antonio, M, McKinney, S, Mathew, V, Ho, B, O'Neil, NJ, Santos, ND, Silvester, J, Wei, V, Garcia, J, Kabeer, F, Lai, D, Soriano, P, Banáth, J, Chiu, DS, Yap, D, Le, DD, Ye, FB, Zhang, A, Thu, K, Soong, J, Lin, SC, Tsai, AHC, Osako, T, Algara, T, Saunders, DN, Wong, J, Xian, J, Bally, MB, Brenton, JD, Brown, GW, Shah, SP, Cescon, D, Mak, TW, Caldas, C, Stirling, PC, Hieter, P, Balasubramanian, S & Aparicio, S 2017, 'CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours', Nature Communications, vol. 8, 14432. https://doi.org/10.1038/ncomms14432

TY - JOUR

T1 - CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours

AU - Xu, Hong

AU - Di Antonio, Marco

AU - McKinney, Steven

AU - Mathew, Veena

AU - Ho, Brandon

AU - O'Neil, Nigel J.

AU - Santos, Nancy Dos

AU - Silvester, Jennifer

AU - Wei, Vivien

AU - Garcia, Jessica

AU - Kabeer, Farhia

AU - Lai, Daniel

AU - Soriano, Priscilla

AU - Banáth, Judit

AU - Chiu, Derek S.

AU - Yap, Damian

AU - Le, Daniel D.

AU - Ye, Frank B.

AU - Zhang, Anni

AU - Thu, Kelsie

AU - Soong, John

AU - Lin, Shu Chuan

AU - Tsai, Angela Hsin Chin

AU - Osako, Tomo

AU - Algara, Teresa

AU - Saunders, Darren N.

AU - Wong, Jason

AU - Xian, Jian

AU - Bally, Marcel B.

AU - Brenton, James D.

AU - Brown, Grant W.

AU - Shah, Sohrab P.

AU - Cescon, David

AU - Mak, Tak W.

AU - Caldas, Carlos

AU - Stirling, Peter C.

AU - Hieter, Phil

AU - Balasubramanian, Shankar

AU - Aparicio, Samuel

PY - 2017/2/17

Y1 - 2017/2/17

N2 - 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).

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).

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AN - SCOPUS:85013159255

SN - 2041-1723

VL - 8

JO - Nature Communications

JF - Nature Communications

M1 - 14432

ER -

CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours

Abstract

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