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

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 resi...

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Published in:Cell reports (Cambridge) Vol. 42; no. 5; p. 112538
Main Authors: Bhin, Jinhyuk, Paes Dias, Mariana, Gogola, Ewa, Rolfs, Frank, Piersma, Sander R., de Bruijn, Roebi, de Ruiter, Julian R., van den Broek, Bram, Duarte, Alexandra A., Sol, Wendy, van der Heijden, Ingrid, Andronikou, Christina, Kaiponen, Taina S., Bakker, Lara, Lieftink, Cor, Morris, Ben, Beijersbergen, Roderick L., van de Ven, Marieke, Jimenez, Connie R., Wessels, Lodewyk F.A., Rottenberg, Sven, Jonkers, Jos
Format: Journal Article
Language:English
Published: United States Elsevier Inc 30.05.2023
Cell Press
Elsevier
Subjects:
BRCA1
BRCA2
breast cancer
CP: Cancer
homologous recombination
multi-omics
PARP inhibitor
therapy resistance
homologous recombination
CP: Cancer
PARP inhibitor
multi-omics
breast cancer
BRCA1
BRCA2
therapy resistance
ISSN:2211-1247, 2211-1247
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Summary: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. [Display omitted] •HR recovery drives PARPi resistance in BRCA1-KO tumors but not in BRCA2-KO tumors•HR recovery in PARPi-resistant BRCA1-KO tumors occurs mostly via 53BP1 loss•HR-deficient PARPi-resistant BRCA1-KO tumors show increased immune infiltration•PARG loss is the most common alteration in PARPi-resistant BRCA2-deficient tumors Bhin et al. use multi-omics and HR analysis of matched treatment-naive and PARPi-resistant BRCA1/2-KO mouse tumors to investigate non-reversion mechanisms driving spontaneous resistance in vivo. HR restoration via 53BP1 loss and restoration of PARP signaling via PARG loss are the two dominant resistance mechanisms in BRCA1-KO and BRCA2-KO tumors, respectively.
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ISSN:2211-1247
2211-1247
DOI:10.1016/j.celrep.2023.112538