@article{f5b27ddd731045c6bf738187bb844cd7,
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 = "https://doi.org/10.1016/j.celrep.2023.112538",
language = "English",
volume = "42",
journal = "Cell reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}