Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors

Jinhyuk Bhin; Mariana Paes Dias; Ewa Gogola; Frank Rolfs; Sander R. Piersma; Roebi de Bruijn; Julian R. de Ruiter; Bram van den Broek; Alexandra A. Duarte; Wendy Sol; Ingrid van der Heijden; Christina Andronikou; Taina S. Kaiponen; Lara Bakker; Cor Lieftink; Ben Morris; Roderick L. Beijersbergen; Marieke van de Ven; Connie R. Jimenez; Lodewyk F. A. Wessels; Sven Rottenberg; Jos Jonkers

doi:10.1016/j.celrep.2023.112538

Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors

Jinhyuk Bhin
, Mariana Paes Dias
, Ewa Gogola
, Frank Rolfs
, Sander R. Piersma
, Roebi de Bruijn
, Julian R. de Ruiter
, Bram van den Broek
, Alexandra A. Duarte
, Wendy Sol
, Ingrid van der Heijden
, Christina Andronikou
, Taina S. Kaiponen
, Lara Bakker
, Cor Lieftink
, Ben Morris
, Roderick L. Beijersbergen
, Marieke van de Ven
, Connie R. Jimenez
, Lodewyk F. A. Wessels^*

Sven Rottenberg^*, Jos Jonkers^*

^*Corresponding author for this work

Netherlands Cancer Institute
Yonsei University
University of Bern
University of Bern, Institute of Animal Pathology

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

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Abstract

BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.

Original language	English
Article number	112538
Journal	Cell reports
Volume	42
Issue number	5
DOIs	https://doi.org/10.1016/j.celrep.2023.112538
Publication status	Published - 30 May 2023

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

BRCA1
BRCA2
CP: Cancer
PARP inhibitor
breast cancer
homologous recombination
multi-omics
therapy resistance

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Multi-omics-analysis-reveals-distinct-non-reversion-mechanisms-of-parpi-resistance-in-brca1--versus-brca2-deficient-mamm.pdfFinal published version, 7.08 MBLicence: CC BY

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Bhin, J., Paes Dias, M., Gogola, E., Rolfs, F., Piersma, S. R., de Bruijn, R., de Ruiter, J. R., van den Broek, B., Duarte, A. A., Sol, W., van der Heijden, I., Andronikou, C., Kaiponen, T. S., Bakker, L., Lieftink, C., Morris, B., Beijersbergen, R. L., van de Ven, M., Jimenez, C. R., ... Jonkers, J. (2023). Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors. Cell reports, 42(5), Article 112538. https://doi.org/10.1016/j.celrep.2023.112538

@article{13d3df97bac14f62a60d3cf4cb353fd9,

title = "Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors",

abstract = "BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62\% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.",

keywords = "BRCA1, BRCA2, CP: Cancer, PARP inhibitor, breast cancer, homologous recombination, multi-omics, therapy resistance",

author = "Jinhyuk Bhin and \{Paes Dias\}, Mariana and Ewa Gogola and Frank Rolfs and Piersma, \{Sander R.\} and \{de Bruijn\}, Roebi and \{de Ruiter\}, \{Julian R.\} and \{van den Broek\}, Bram and Duarte, \{Alexandra A.\} and Wendy Sol and \{van der Heijden\}, Ingrid and Christina Andronikou and Kaiponen, \{Taina S.\} and Lara Bakker and Cor Lieftink and Ben Morris and Beijersbergen, \{Roderick L.\} and \{van de Ven\}, Marieke and Jimenez, \{Connie R.\} and Wessels, \{Lodewyk F. A.\} and Sven Rottenberg and Jos Jonkers",

note = "Funding Information: We thank the members of the Preclinical Intervention Unit of the Mouse Clinic for Cancer and Aging (MCCA) at the NKI for their technical support with the animal studies. We also thank the NKI Animal Pathology facility and the Comparative Pathology (COMPATH) and Translational Research (TRU) units at the University of Bern for their technical support with the immunohistochemistry and the NKI Digital Microscopy facility, Genomics Core facility, and Animal facility for their excellent service. We would like to thank Piet Borst (NKI, Amsterdam) for scientific discussions. This work was funded by the Oncode Institute ; the Dutch Cancer Society ( KWF 2011-5220 , 2014-6532 , and 2017-61169 ); the Netherlands Organization for Scientific Research ( VICI 91814643 ); the Netherlands Genomics Initiative ( 93512009 ); the Swiss National Science Foundation ( 310030\_179360 ); the Swiss Cancer League ( KFS-5519-02-2022 ); the Wilhelm-Sander Foundation (no. 2019.069.1 ); and the European Research Council ( ERC-2019-AdG-883877 , SyG-319661 ). Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = may,

day = "30",

doi = "10.1016/j.celrep.2023.112538",

language = "English",

volume = "42",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

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}

Bhin, J, Paes Dias, M, Gogola, E, Rolfs, F, Piersma, SR, de Bruijn, R, de Ruiter, JR, van den Broek, B, Duarte, AA, Sol, W, van der Heijden, I, Andronikou, C, Kaiponen, TS, Bakker, L, Lieftink, C, Morris, B, Beijersbergen, RL, van de Ven, M, Jimenez, CR, Wessels, LFA, Rottenberg, S & Jonkers, J 2023, 'Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors', Cell reports, vol. 42, no. 5, 112538. https://doi.org/10.1016/j.celrep.2023.112538

TY - JOUR

T1 - Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors

AU - Bhin, Jinhyuk

AU - Paes Dias, Mariana

AU - Gogola, Ewa

AU - Rolfs, Frank

AU - Piersma, Sander R.

AU - de Bruijn, Roebi

AU - de Ruiter, Julian R.

AU - van den Broek, Bram

AU - Duarte, Alexandra A.

AU - Sol, Wendy

AU - van der Heijden, Ingrid

AU - Andronikou, Christina

AU - Kaiponen, Taina S.

AU - Bakker, Lara

AU - Lieftink, Cor

AU - Morris, Ben

AU - Beijersbergen, Roderick L.

AU - van de Ven, Marieke

AU - Jimenez, Connie R.

AU - Wessels, Lodewyk F. A.

AU - Rottenberg, Sven

AU - Jonkers, Jos

N1 - Funding Information: We thank the members of the Preclinical Intervention Unit of the Mouse Clinic for Cancer and Aging (MCCA) at the NKI for their technical support with the animal studies. We also thank the NKI Animal Pathology facility and the Comparative Pathology (COMPATH) and Translational Research (TRU) units at the University of Bern for their technical support with the immunohistochemistry and the NKI Digital Microscopy facility, Genomics Core facility, and Animal facility for their excellent service. We would like to thank Piet Borst (NKI, Amsterdam) for scientific discussions. This work was funded by the Oncode Institute ; the Dutch Cancer Society ( KWF 2011-5220 , 2014-6532 , and 2017-61169 ); the Netherlands Organization for Scientific Research ( VICI 91814643 ); the Netherlands Genomics Initiative ( 93512009 ); the Swiss National Science Foundation ( 310030_179360 ); the Swiss Cancer League ( KFS-5519-02-2022 ); the Wilhelm-Sander Foundation (no. 2019.069.1 ); and the European Research Council ( ERC-2019-AdG-883877 , SyG-319661 ). Publisher Copyright: © 2023 The Author(s)

PY - 2023/5/30

Y1 - 2023/5/30

N2 - BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.

AB - BRCA1 and BRCA2 both function in DNA double-strand break repair by homologous recombination (HR). Due to their HR defect, BRCA1/2-deficient cancers are sensitive to poly(ADP-ribose) polymerase inhibitors (PARPis), but they eventually acquire resistance. Preclinical studies yielded several PARPi resistance mechanisms that do not involve BRCA1/2 reactivation, but their relevance in the clinic remains elusive. To investigate which BRCA1/2-independent mechanisms drive spontaneous resistance in vivo, we combine molecular profiling with functional analysis of HR of matched PARPi-naive and PARPi-resistant mouse mammary tumors harboring large intragenic deletions that prevent reactivation of BRCA1/2. We observe restoration of HR in 62% of PARPi-resistant BRCA1-deficient tumors but none in the PARPi-resistant BRCA2-deficient tumors. Moreover, we find that 53BP1 loss is the prevalent resistance mechanism in HR-proficient BRCA1-deficient tumors, whereas resistance in BRCA2-deficient tumors is mainly induced by PARG loss. Furthermore, combined multi-omics analysis identifies additional genes and pathways potentially involved in modulating PARPi response.

KW - BRCA1

KW - BRCA2

KW - CP: Cancer

KW - PARP inhibitor

KW - breast cancer

KW - homologous recombination

KW - multi-omics

KW - therapy resistance

UR - https://www.scopus.com/pages/publications/85159894233

U2 - 10.1016/j.celrep.2023.112538

DO - 10.1016/j.celrep.2023.112538

M3 - Article

C2 - 37209095

SN - 2211-1247

VL - 42

JO - Cell reports

JF - Cell reports

IS - 5

M1 - 112538

ER -

Multi-omics analysis reveals distinct non-reversion mechanisms of PARPi resistance in BRCA1- versus BRCA2-deficient mammary tumors

Abstract

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Keywords

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