CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer

Elaine Sanij; Katherine M. Hannan; Jiachen Xuan; Shunfei Yan; Jessica E. Ahern; Anna S. Trigos; Natalie Brajanovski; Jinbae Son; Keefe T. Chan; Olga Kondrashova; Elizabeth Lieschke; Matthew J. Wakefield; Daniel Frank; Sarah Ellis; Carleen Cullinane; Jian Kang; Gretchen Poortinga; Purba Nag; Andrew J. Deans; Kum Kum Khanna; Linda Mileshkin; Grant A. McArthur; John Soong; Els M.J.J. Berns; Ross D. Hannan; Clare L. Scott; Karen E. Sheppard; Richard B. Pearson

doi:10.1038/s41467-020-16393-4

CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer

Elaine Sanij^*, Katherine M. Hannan, Jiachen Xuan, Shunfei Yan, Jessica E. Ahern, Anna S. Trigos, Natalie Brajanovski, Jinbae Son, Keefe T. Chan, Olga Kondrashova, Elizabeth Lieschke, Matthew J. Wakefield, Daniel Frank, Sarah Ellis, Carleen Cullinane, Jian Kang, Gretchen Poortinga, Purba Nag, Andrew J. Deans, Kum Kum KhannaLinda Mileshkin, Grant A. McArthur, John Soong, Els M.J.J. Berns, Ross D. Hannan, Clare L. Scott, Karen E. Sheppard, Richard B. Pearson

^*Corresponding author for this work

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

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Abstract

Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.

Original language	English
Article number	2641
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-16393-4
Publication status	Published - 1 Dec 2020

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Sanij, E., Hannan, K. M., Xuan, J., Yan, S., Ahern, J. E., Trigos, A. S., Brajanovski, N., Son, J., Chan, K. T., Kondrashova, O., Lieschke, E., Wakefield, M. J., Frank, D., Ellis, S., Cullinane, C., Kang, J., Poortinga, G., Nag, P., Deans, A. J., ... Pearson, R. B. (2020). CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer. Nature Communications, 11(1), Article 2641. https://doi.org/10.1038/s41467-020-16393-4

@article{a962a1217d9241d1bcc02a0fe138a4df,

title = "CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer",

abstract = "Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.",

author = "Elaine Sanij and Hannan, {Katherine M.} and Jiachen Xuan and Shunfei Yan and Ahern, {Jessica E.} and Trigos, {Anna S.} and Natalie Brajanovski and Jinbae Son and Chan, {Keefe T.} and Olga Kondrashova and Elizabeth Lieschke and Wakefield, {Matthew J.} and Daniel Frank and Sarah Ellis and Carleen Cullinane and Jian Kang and Gretchen Poortinga and Purba Nag and Deans, {Andrew J.} and Khanna, {Kum Kum} and Linda Mileshkin and McArthur, {Grant A.} and John Soong and Berns, {Els M.J.J.} and Hannan, {Ross D.} and Scott, {Clare L.} and Sheppard, {Karen E.} and Pearson, {Richard B.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1038/s41467-020-16393-4",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

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Sanij, E, Hannan, KM, Xuan, J, Yan, S, Ahern, JE, Trigos, AS, Brajanovski, N, Son, J, Chan, KT, Kondrashova, O, Lieschke, E, Wakefield, MJ, Frank, D, Ellis, S, Cullinane, C, Kang, J, Poortinga, G, Nag, P, Deans, AJ, Khanna, KK, Mileshkin, L, McArthur, GA, Soong, J, Berns, EMJJ, Hannan, RD, Scott, CL, Sheppard, KE & Pearson, RB 2020, 'CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer', Nature Communications, vol. 11, no. 1, 2641. https://doi.org/10.1038/s41467-020-16393-4

TY - JOUR

T1 - CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer

AU - Sanij, Elaine

AU - Hannan, Katherine M.

AU - Xuan, Jiachen

AU - Yan, Shunfei

AU - Ahern, Jessica E.

AU - Trigos, Anna S.

AU - Brajanovski, Natalie

AU - Son, Jinbae

AU - Chan, Keefe T.

AU - Kondrashova, Olga

AU - Lieschke, Elizabeth

AU - Wakefield, Matthew J.

AU - Frank, Daniel

AU - Ellis, Sarah

AU - Cullinane, Carleen

AU - Kang, Jian

AU - Poortinga, Gretchen

AU - Nag, Purba

AU - Deans, Andrew J.

AU - Khanna, Kum Kum

AU - Mileshkin, Linda

AU - McArthur, Grant A.

AU - Soong, John

AU - Berns, Els M.J.J.

AU - Hannan, Ross D.

AU - Scott, Clare L.

AU - Sheppard, Karen E.

AU - Pearson, Richard B.

PY - 2020/12/1

Y1 - 2020/12/1

N2 - Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.

AB - Acquired resistance to PARP inhibitors (PARPi) is a major challenge for the clinical management of high grade serous ovarian cancer (HGSOC). Here, we demonstrate CX-5461, the first-in-class inhibitor of RNA polymerase I transcription of ribosomal RNA genes (rDNA), induces replication stress and activates the DNA damage response. CX-5461 co-operates with PARPi in exacerbating replication stress and enhances therapeutic efficacy against homologous recombination (HR) DNA repair-deficient HGSOC-patient-derived xenograft (PDX) in vivo. We demonstrate CX-5461 has a different sensitivity spectrum to PARPi involving MRE11-dependent degradation of replication forks. Importantly, CX-5461 exhibits in vivo single agent efficacy in a HGSOC-PDX with reduced sensitivity to PARPi by overcoming replication fork protection. Further, we identify CX-5461-sensitivity gene expression signatures in primary and relapsed HGSOC. We propose CX-5461 is a promising therapy in combination with PARPi in HR-deficient HGSOC and also as a single agent for the treatment of relapsed disease.

UR - http://www.scopus.com/inward/record.url?scp=85085396637&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-16393-4

DO - 10.1038/s41467-020-16393-4

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2641

ER -

CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer

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